A method and device for generating control instructions for a 96-channel polypeptide synthesizer

Abstract

The present application relates to the technical field of polypeptide synthesis automation control, in particular to a 96-channel polypeptide synthesizer control instruction generation method and device.The present application slices a peptide sequence set according to amino acid positions, generates a sliced amino acid demand distribution matrix, takes the sum of the number of adjacent channel pairs required by adjacent active channels on the path in all slices as the optimization target, deduces the optimal access path sequence of the mechanical arm to the 96 channels, divides the legal addition segment and marks the gun head replacement position on this basis, generates AA liquid addition instructions, + addition instructions and gun head replacement instructions in turn, performs end-capping processing on the exit channel, and finally outputs a complete lower machine control instruction sequence.The present application can effectively reduce the number of gun head replacements in the synthesis process and improve the synthesis efficiency.

Description

Technical Field

[0001] This invention relates to the field of automated control technology for peptide synthesis, specifically to a method and apparatus for generating control commands for a 96-channel peptide synthesizer. Background Technology

[0002] Solid-phase peptide synthesis is currently the mainstream method for peptide drug research and production. Its basic principle is to sequentially couple amino acid residues onto a solid-phase carrier resin, gradually extending the peptide chain to the target sequence. The 96-channel peptide synthesizer achieves high-throughput parallel synthesis based on this principle, simultaneously synthesizing peptides of different sequences in 96 independent channels, significantly improving synthesis efficiency and throughput.

[0003] However, parallel synthesis with 96 channels places high demands on the generation of control commands. Different channels often require different types of amino acids in the same synthetic step, necessitating frequent tip changes by the robotic arm when accessing different channels. In existing technologies, robotic arms typically perform access according to a fixed channel number sequence, without optimization for the amino acid distribution required by specific peptide sequences, resulting in numerous unnecessary tip changes and hindering further improvements in synthesis efficiency.

[0004] Furthermore, in a 96-channel synthesis scenario, the peptide sequence lengths of each channel are often not identical. Shorter channels may complete the synthesis of the target sequence midway through the process. If these channels are not promptly capped, the free amino groups will continue to participate in subsequent coupling reactions, affecting product purity. Current control command generation methods lack a systematic management mechanism for these exiting channels, making it difficult to guarantee the integrity and accuracy of each channel's sequence. Summary of the Invention

[0005] This invention provides a method and apparatus for generating control commands for a 96-channel peptide synthesizer, thereby reducing the number of times the robotic arm needs to change nozzles during synthesis and improving synthesis efficiency.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] This invention discloses a method for generating control commands for a 96-channel peptide synthesizer, comprising:

[0008] S100: Receives peptide sequence set and process parameters, slices peptide sequence set according to amino acid position, identifies active channel set for each slice, counts the types of amino acids required for each active channel in the active channel set, and generates slice amino acid demand distribution matrix.

[0009] S200: Based on the amino acid demand distribution matrix of the slice, the channel distribution of amino acid types in each slice is statistically analyzed. The optimization objective is to minimize the sum of the number of adjacent channel pairs with different amino acid types required by adjacent active channels on all slices. The optimal access path sequence for the robotic arm to 96 channels is derived.

[0010] S300: For each slice, arrange the active channels in the active channel set according to the optimal access path sequence, compare the types of amino acids required by adjacent active channels along the path direction, divide the continuous active channels with the same types of required amino acids into the same legal continuation segment, and mark the nozzle change position at the boundary of adjacent legal continuation segments.

[0011] S400: For each valid continuous addition segment, calculate the addition volume based on the resin volume and amino acid parameters of the active channels within the valid continuous addition segment. Generate an AA addition command carrying the addition volume for the first active channel on the path within the valid continuous addition segment. Generate + addition commands sequentially for the subsequent active channels within the valid continuous addition segment. Generate a pipette head change command at the pipette head change position. Combine and output a complete sequence of lower-level machine control commands in the order of preprocessing command block, slicing command block, and postprocessing command block.

[0012] As a preferred embodiment of the present invention, in S100, the process parameters include:

[0013] Channel resin amount;

[0014] Target coupling equivalent;

[0015] Molar mass of amino acids.

[0016] As a preferred embodiment of the present invention, in S100, the slicing step includes:

[0017] The total number of slices is determined by the number of amino acids in the longest sequence within the peptide sequence set.

[0018] Each sequence is numbered sequentially starting from the anchoring end, and amino acids at the same number position in all sequences are grouped into the same slice;

[0019] Channels with a sequence length shorter than the current slice number are not included in the active channel set of the current slice;

[0020] Channels whose sequence length is equal to the current slice number are marked as exit channels.

[0021] As a preferred embodiment of the present invention, in S100, the step of generating the sliced ​​amino acid demand distribution matrix includes:

[0022] Construct a two-dimensional matrix with slice numbers as rows and amino acid types as columns;

[0023] For each slice, iterate through the set of active channels and record the matrix elements corresponding to the types of amino acids required for each active channel as a list of channel numbers containing the current channel number;

[0024] The matrix elements corresponding to amino acid types in the current slice that are not used by any active channels are set to empty.

[0025] As a preferred embodiment of the present invention, in S200, the derivation step of the optimal access path sequence includes:

[0026] The search space is defined by all permutations of the 96 channel numbers;

[0027] For each candidate path sequence, traverse all slices, count the number of adjacent channel pairs with different amino acid types required by adjacent active channels along the path direction, and sum them to obtain the total number of pipette tip changes for the current candidate path sequence across all slices;

[0028] The candidate path sequence with the minimum total number of gun head swaps is selected as the optimal access path sequence.

[0029] As a preferred embodiment of the present invention, in S200, the derivation step of the optimal access path sequence further includes:

[0030] The slice amino acid demand distribution matrix is ​​transformed into a channel similarity matrix. The elements of the channel similarity matrix are the number of slices in which the two channels have the same amino acid type in all slices.

[0031] Using the channel similarity matrix as input, a greedy strategy is adopted to append the unvisited channel with the highest similarity to the end channel of the current path to the path in turn. When the similarity is the same, the channel with the smaller channel number is selected to obtain the initial path sequence.

[0032] Swap the positions of any two channels in the initial path sequence. If the total number of times the nozzle is changed across all slices decreases after the swap, the swap is accepted. Repeat this process until the total number of times the nozzle is changed across all slices no longer decreases, and the optimal access path sequence is obtained.

[0033] As a preferred embodiment of the present invention, in S300, the step of dividing the legal continuation segment includes:

[0034] Arrange the set of active channels of the current slice according to the optimal access path sequence to obtain an ordered list of active channels of the current slice;

[0035] Starting from the first channel in the ordered list of active channels, compare the types of amino acids required for the current channel with the next active channel on the path.

[0036] If the amino acid types are the same, the next active channel will be assigned to the current valid continuation segment;

[0037] If the amino acid type is different, the current legal addition segment ends and a new legal addition segment begins with the next active channel.

[0038] After traversing the ordered list of active channels, we obtain all valid continuation segments and gun-head switching positions for the current slice.

[0039] As a preferred embodiment of the present invention, in S400, the step of calculating the amount of liquid added includes:

[0040] The total amount of liquid added in the AA liquid addition command is calculated by taking the sum of the resin volume of all active channels in the legal addition segment, the target coupling equivalent, and the molar mass of amino acids required by the active channels in the legal addition segment as inputs.

[0041] Using the amount of resin in a single active channel within the legal continuous addition segment, the target coupling equivalent, and the molar mass of amino acids required for the active channel within the legal continuous addition segment as inputs, calculate the single addition volume of the + addition command.

[0042] Write the total liquid volume into the liquid volume parameter of the AA liquid addition command, and write the single liquid volume into the liquid volume parameter of the + continue addition command.

[0043] As a preferred embodiment of the present invention, in S400, the processing method for the exit channel includes:

[0044] After all the amino acid addition instructions for the slice containing the exit channel are generated, an acetic anhydride addition instruction for the exit channel is generated to cap the free amino groups in the exit channel.

[0045] After the endcapping is completed, the exit channel will be removed from the set of active channels for all subsequent slices;

[0046] Subsequent slices will no longer generate any instructions for exiting the channel.

[0047] The present invention also proposes a control command generation device for a 96-channel peptide synthesizer, the device comprising:

[0048] Demand Analysis Module: Receives peptide sequence set and process parameters, slices the peptide sequence set according to amino acid position, identifies active channel set for each slice, counts the types of amino acids required for each active channel in the active channel set, and generates slice amino acid demand distribution matrix;

[0049] Path optimization module: Based on the slice amino acid demand distribution matrix, the channel distribution of amino acid types in each slice is statistically analyzed. The optimization objective is to minimize the sum of the number of adjacent channel pairs with different amino acid types required by adjacent active channels on all slices. The optimal access path sequence for the robotic arm to 96 channels is derived.

[0050] The continuous segment division module: For each slice, the active channels in the active channel set are arranged according to the optimal access path sequence. The required amino acid types of adjacent active channels on the path are compared sequentially along the path direction. The active channels that are continuous on the path and have the same required amino acid types are divided into the same legal continuous segment. The nozzle change position is marked at the boundary of adjacent legal continuous segments.

[0051] Instruction generation module: For each valid continuous addition segment, calculate the addition volume based on the resin volume and amino acid parameters of the active channels within the valid continuous addition segment. Generate an AA addition instruction carrying the addition volume for the first active channel on the path within the valid continuous addition segment. Generate + addition instructions sequentially for subsequent active channels within the valid continuous addition segment. Generate a pipette head change instruction at the pipette head change position. Combine and output a complete sequence of lower-level machine control instructions in the order of preprocessing instruction block, slicing instruction block, and postprocessing instruction block.

[0052] The beneficial effects of this invention are:

[0053] 1. This invention constructs a slice amino acid demand distribution matrix and combines a greedy strategy with pairwise swapping optimization to derive the optimal access path sequence. This precisely matches the robotic arm access order with the amino acid demand distribution of the peptide sequence set. Compared with the existing method of accessing in a fixed numbered order, this systematically reduces the number of pipette head changes and improves synthesis efficiency.

[0054] 2. By introducing an exit channel capping mechanism and deeply integrating it with the legal continuation segment division and instruction generation process, this invention achieves precise control over peptide sequences of different lengths, ensuring the integrity of each channel sequence and the accuracy of instruction generation in a 96-channel parallel synthesis scenario. Attached Figure Description

[0055] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used in conjunction with embodiments of the invention to explain the invention and do not constitute a limitation thereof. In the drawings:

[0056] Figure 1 This is a flowchart illustrating a method for generating control commands for a 96-channel peptide synthesizer according to the present invention.

[0057] Figure 2 This is a schematic diagram of the control command generation device for a 96-channel peptide synthesizer according to the present invention. Detailed Implementation

[0058] The preferred embodiments of the present invention will be described below with reference to the accompanying drawings. It should be understood that the preferred embodiments described herein are for illustration and explanation only and are not intended to limit the present invention.

[0059] Example 1: As Figure 1As shown, the present invention provides a method for generating control commands for a 96-channel peptide synthesizer, comprising:

[0060] S100: Receives peptide sequence set and process parameters, slices peptide sequence set according to amino acid position, identifies active channel set for each slice, counts the types of amino acids required for each active channel in the active channel set, and generates slice amino acid demand distribution matrix.

[0061] Specifically, receiving peptide sequence sets , Composed of up to 96 peptide sequences, denoted as ,in This represents the number of valid sequences in the peptide sequence set. Each sequence It consists of single-letter codes for several amino acid residues arranged sequentially. The position number in the peptide sequence set is the channel number corresponding to the synthesis of that sequence; unused channels are not included in the peptide sequence set.

[0062] Furthermore, the process parameters include the amount of channel resin, the target coupling equivalent, and the molar mass of amino acids, wherein the amount of channel resin... For the first The mass of the solid-phase carrier resin in the channel, in mg, can be set independently for each channel; target coupling equivalent. This is the ratio of the molar amount of amino acid to the molar amount of resin, reflecting the degree of excess of amino acid relative to resin, and is a global parameter; the molar mass of amino acid... amino acids The molar mass of the activated form, in g / mol, is stored in a dictionary format using amino acid single-letter codes as bonds. The above three process parameters are used in the liquid addition calculation in S400 and are fully received and stored in S100.

[0063] Furthermore, the slicing steps are as follows: solid-phase polypeptide synthesis extends progressively from the anchored end to the free end, therefore for each sequence... Numbering starts from the anchoring end, with the first position representing the first amino acid residue coupled, and so on. The last amino acid residue to be coupled is located at position 1. For sequence Length of slices. Total number of slices. The number of amino acids in the longest sequence from the peptide sequence set:

[0064] ;

[0065] in For sequence Length, This represents the number of valid sequences in the peptide sequence set. Slice numbers are generated sequentially, with all sequences at the same number position. The amino acid residues were classified into the slices. .

[0066] slices Identify its active channel set Sequence length Not less than the slice number Channel included Sequence length Less than slice number The channel is not included Sequence length equal to slice number The channel is in the process of slicing After the coupling sequence is synthesized, it is marked as the exit channel. The processing method for the exit channel is described in S400.

[0067] In one implementation, let the sequence of channel 1 be... It is ACD. ; Sequence of Channel 2 For ACDE, ; Sequence of channel 3 AC, Then the total number of slices The active channel set and exit channel set for each slice are shown in Table 1 below.

[0068]

[0069] Furthermore, the sliced ​​amino acid demand distribution matrix The generation steps are as follows: construct a two-dimensional matrix with slice number as the row and amino acid type as the column. The row index is the slice number. The column index is based on the amino acid type. , This represents the set of all amino acid types involved in the current peptide sequence. For each slice... Traverse the set of active channels The matrix elements corresponding to the types of amino acids required for each active channel. The record is a list of channel numbers containing the current channel number:

[0070] ;

[0071] in Number the slices. For amino acid types, For slices The collection of active channels For sequence No. Amino acid residues at position 1. Slice Matrix elements corresponding to amino acid types not used by any active channels Leave blank.

[0072] In one implementation, following the three-channel example described above, the generated slice amino acid demand distribution matrix... As shown in the table below, blank spaces in the table indicate that the corresponding matrix element is empty.

[0073]

[0074] amino acid demand distribution matrix for slices It fully describes the channel distribution required by each amino acid in each slice, serving as the input data structure for S200 path optimization.

[0075] S200: Based on the amino acid demand distribution matrix of the slice, the channel distribution of amino acid types in each slice is statistically analyzed. The optimization objective is to minimize the sum of the number of adjacent channel pairs with different amino acid types required by adjacent active channels on all slices. The optimal access path sequence for the robotic arm to 96 channels is derived.

[0076] Specifically, S200 is based on the sliced ​​amino acid demand distribution matrix. The optimal access path sequence for the robotic arm to access 96 channels was derived with the goal of minimizing the sum of the number of adjacent channel pairs with different amino acid types required for adjacent active channels in all slices.

[0077] First, define the access path sequence. A permutation of 96 channel numbers, denoted as ,in For the first on the path The channel number for each location. The robotic arm presses... The channels are accessed in sequence.

[0078] For a given access path sequence and slices Two adjacent channels on the path and This forms an adjacent channel pair. If and All belong to slices active channel set Furthermore, the two require different types of amino acids, namely... Then the adjacent channel pair in the slice One nozzle change occurred. Total number of nozzle changes. Defined as access path sequence The optimal access path sequence is the sum of the number of head changes generated across all slices. In order to make The access path sequence that yields the minimum value.

[0079] Furthermore, the derivation steps of the optimal access path sequence are as follows: using the full permutation of the 96 channel numbers as the search space, for each candidate path sequence... Traverse all slices, count the number of adjacent channel pairs with different amino acid types required by adjacent active channels along the path, and sum them to obtain the total number of pipette tip changes. ,Pick The smallest candidate path sequence is taken as the optimal access path sequence. .

[0080] Furthermore, since the total number of permutations of 96 channels is too large, direct enumeration is not practically feasible. The derivation steps of the optimal access path sequence also include the following heuristic solution process:

[0081] The first step is to create a matrix of amino acid demand distribution for sliced ​​amino acids. Convert to channel similarity matrix . It is a 96th order square matrix, with elements For channel With channel The number of slices with the same amino acid composition required in all slices, i.e.:

[0082] ;

[0083] in Number the slices. For slices The collection of active channels For sequence No. Amino acid residues at position 1. The larger the value, the better the channel. With channel The higher the consistency of the required amino acid types in each slice, the fewer times the pipette tip needs to be changed when they are adjacent on the path.

[0084] The second step is to use the channel similarity matrix. As input, an initial path sequence is constructed using a greedy strategy. Arbitrarily select a channel as the starting point of the path, and sequentially add the unvisited channels with the highest similarity to the channel at the end of the current path to the end of the path; when multiple unvisited channels have the same similarity, take the channel with the smaller number; continue until all 96 channels have been added to the path, and obtain the initial path sequence. .

[0085] The third step is to process the initial path sequence. Perform pairwise swap optimization: for any two positions in the path and The channels are swapped, and the total number of gun head swaps is calculated after the swap. If the total number of gun head swaps is... If the value decreases, accept the swap and update the current path sequence. Repeat the above swap operation until no position pair can be found that allows... Continue reducing the number of swaps until the final path sequence is taken as the optimal access path sequence. .

[0086] In one embodiment, the peptide sequence set has four channels, with sequences AC, AD, BC, and BD, and the number of slices... In slice 1, channel 1 requires A, channel 2 requires A, channel 3 requires B, and channel 4 requires B. In slice 2, channel 1 requires C, channel 2 requires D, channel 3 requires C, and channel 4 requires D. Channel similarity matrix. As shown in the table below.

[0087]

[0088] Starting with channel 1, a greedy strategy is used to sequentially add unvisited channels with the highest similarity. When multiple unvisited channels have the same similarity to the last channel of the current path, the channel with the smaller number is selected to obtain the initial path sequence. After testing by swapping each pair of positions in the path, it was found that attempting to swap all positions one by one could not further reduce the total number of gun head swaps. Therefore, the current path sequence is a local optimum, and the optimal access path sequence is determined. The required amino acid types for adjacent channels on slice 1 are AA, AB, and BB in sequence, and CD, DD, and DC in sequence on slice 2. The total number of pipette tip changes is 3.

[0089] S300: For each slice, arrange the active channels in the active channel set according to the optimal access path sequence, compare the types of amino acids required by adjacent active channels along the path direction, divide the continuous active channels with the same types of required amino acids into the same legal continuation segment, and mark the nozzle change position at the boundary of adjacent legal continuation segments.

[0090] Specifically, for each slice, based on the optimal access path sequence For active channel set Perform legal segmentation and mark the gun head replacement position.

[0091] Furthermore, the steps for dividing the legal continuation segment are as follows:

[0092] slice active channel set The channels in the optimal access path sequence Arrange them in order to obtain slices. Ordered list of active channels Specifically, traverse sequentially. The channel numbers in the data will belong to The channel according to its Arranged in the order of appearance It does not belong to The channel is skipped. Let... The length is ,but ,in For the first in the ordered active channel list The channel number.

[0093] from The first passage Rise, with Start the first valid continuation segment from the beginning. Then proceed sequentially... Adjacent channel pairs in the middle position Compare them. :like That is, the two in the slice If the required amino acid types are the same, then... If it is included in the current valid continuation segment; That is, the two in the slice If the required amino acid type is different, then the current legal addition segment ends, and... and Mark the gun head replacement position at the boundary between them, and use... Start a new valid continuation segment from the beginning. After traversing all segments... After that, slices were obtained. All legal extension segments and all gun head replacement positions. For sequence No. Amino acid residues at position 1.

[0094] In one implementation, following the four-channel example in S200, the optimal access path sequence is... Slice 1 is divided into valid continuation segments. The set of active channels for slice 1 is then determined. ,according to Arranged active channel table The types of amino acids required for each channel in slice 1 are as follows: Channel 1 requires A, Channel 2 requires A, Channel 4 requires B, and Channel 3 requires B. Adjacent channel pairs are compared sequentially: if Channel 1 and Channel 2 require the same types of amino acids, Channel 2 is added to the current valid continuation segment; if Channel 2 and Channel 4 require different types of amino acids, the current valid continuation segment ends, the pipette tip change position is marked, and a new valid continuation segment begins with Channel 4; if Channel 4 and Channel 3 require the same types of amino acids, Channel 3 is added to the current valid continuation segment. After traversal, slice 1 has two valid continuation segments: {Channel 1, Channel 2} and {Channel 4, Channel 3}, with the pipette tip change position located between Channel 2 and Channel 4.

[0095] Divide slice 2 into valid continuation segments. The set of active channels for slice 2. ,according to Ordered list of active channels The amino acid types required for each channel in slice 2 are as follows: Channel 1 requires C, Channel 2 requires D, Channel 4 requires D, and Channel 3 requires C. Adjacent channel pairs are compared sequentially: if the amino acid types required for Channel 1 and Channel 2 are different, the first valid continuation segment ends, the pipette tip change position is marked, and a new valid continuation segment begins with Channel 2; if the amino acid types required for Channel 2 and Channel 4 are the same, Channel 4 is added to the current valid continuation segment; if the amino acid types required for Channel 4 and Channel 3 are different, the current valid continuation segment ends, the pipette tip change position is marked, and a new valid continuation segment begins with Channel 3. After traversal, slice 2 has three valid continuation segments: {Channel 1}, {Channel 2, Channel 4}, and {Channel 3}, with the pipette tip change position located between Channel 1 and Channel 2, and between Channel 4 and Channel 3.

[0096] Optimal access path sequence The total number of nozzle changes on the two slices was 3. After pairwise swapping, it was confirmed that the local optimum was reached, thus verifying the effectiveness of the S200 path optimization.

[0097] S400: For each valid continuous addition segment, calculate the addition volume based on the resin volume and amino acid parameters of the active channels within the valid continuous addition segment. Generate an AA addition command carrying the addition volume for the first active channel on the path within the valid continuous addition segment. Generate + addition commands sequentially for the subsequent active channels within the valid continuous addition segment. Generate a pipette head change command at the pipette head change position. Combine and output a complete sequence of lower-level machine control commands in the order of preprocessing command block, slicing command block, and postprocessing command block.

[0098] Specifically, for slices Given a valid continuation segment, let the active channels contained in this valid continuation segment be arranged in an ordered list of active channels. The order in is as follows: ,common One active channel, all active channels within this valid continuation segment are in the slice. All required amino acids are .

[0099] Furthermore, the steps for calculating the amount of liquid to be added are as follows:

[0100] The sum of the channel resin amounts of all active channels within the legally added segment and the target coupling equivalent. and amino acids molar mass of amino acids As input, calculate the total liquid volume added for the AA liquid addition command. To legally continue the segment to a single active channel. Channel resin amount Target-coupled equivalent and amino acids molar mass of amino acids As input, calculate the single liquid addition volume for the "+Continue" command corresponding to this channel. ,in Total liquid volume added With each single liquid addition volume The calculations are all based on the product of the target coupling equivalent and the resin molar amount, multiplied by the amino acid molar mass, which is a conventional formulation calculation in this field and will not be elaborated here.

[0101] Based on the above liquid addition calculation results, the steps to generate instructions for a valid continuous addition segment are as follows:

[0102] The first active channel on the path Generates AA liquid addition instructions, which carry the amino acid types. Channel number Single addition volume and total liquid volume To legally continue adding active channels within the segment. One "+" instruction is generated sequentially for each channel, each instruction carrying the corresponding channel number and the single dispensing volume for that channel. A nozzle change instruction is generated at the nozzle change position at the boundary of adjacent valid dispensing segments.

[0103] Furthermore, the processing method for exit channels is as follows: After all amino acid addition instructions for the slice containing the exit channel are generated, an acetic anhydride addition instruction for the exit channel is generated to cap the free amino groups in the exit channel; after capping, the exit channel is removed from the active channel set of all subsequent slices, and no further instructions are generated for the exit channel in subsequent slices.

[0104] The complete sequence of lower-level machine control instructions is output in the order of preprocessing instruction block, slicing instruction block, and postprocessing instruction block. The preprocessing instruction block corresponds to the instruction sequence generated by the preprocessing method before slice 1; the slicing instruction block is the instruction sequence generated sequentially for each slice, and the instruction sequence for each slice includes deprotection step instructions, washing step instructions, amino acid addition instructions, and post-coupling washing instructions; the postprocessing instruction block corresponds to the instruction sequence generated by the postprocessing method after all slices are completed.

[0105] In one implementation, following the four-channel example in S300, instructions are generated for the legal continuation segment {channel 2, channel 4} of slice 2. The required amino acid type for this legal continuation segment is D, the first active channel on the path is channel 2, and the subsequent active channel is channel 4. Let the amount of channel resin in channel 2 be... mg, channel resin amount in channel 4 mg, target coupling equivalent The molar mass of amino acid D g / mol. Based on conventional formulation calculation methods in the field of solid-phase peptide synthesis, and using... mg, mg, , Based on the g / mol and equipment standard resin loading and amino acid solution concentration parameters, the total liquid volume added according to the AA liquid addition command is calculated. Single liquid addition volume of channel 2 and the single liquid addition volume of channel 4 The specific values ​​are then written into the corresponding liquid addition parameters of the instruction. Thus, the AA liquid addition instruction carries the amino acid type D, channel number 2, and single liquid addition volume. and total liquid volume The "+Continue Adding" command carries channel number 4 and the single addition volume. The specific values ​​for the above-mentioned liquid addition volume are calculated based on the actual resin loading and amino acid solution concentration parameters of the equipment and then entered. Subsequently, a nozzle change command is generated at the nozzle change position between channel 4 and channel 3 to begin processing the next valid addition segment {channel 3}.

[0106] In summary, this embodiment provides a method for generating control commands for a 96-channel peptide synthesizer. By slicing the peptide sequence set according to amino acid positions and constructing a slice amino acid demand distribution matrix, the optimal access path sequence is derived with the goal of minimizing the total number of pipette tip changes. Based on this, a valid continuation segment is divided, and AA liquid addition commands, + continuation commands, and pipette tip change commands are generated sequentially. Finally, a complete lower-level machine control command sequence is output by combining the preprocessing command block, slicing command block, and postprocessing command block in that order. This effectively reduces the frequency of pipette tip changes by the robotic arm while ensuring synthesis accuracy, thereby improving synthesis efficiency.

[0107] Example 2:

[0108] like Figure 2 As shown, this embodiment provides a control command generation device for a 96-channel peptide synthesizer, the device comprising:

[0109] Demand Analysis Module: Receives peptide sequence set and process parameters, slices the peptide sequence set according to amino acid position, identifies active channel set for each slice, counts the types of amino acids required for each active channel in the active channel set, and generates slice amino acid demand distribution matrix;

[0110] Path optimization module: Based on the slice amino acid demand distribution matrix, the channel distribution of amino acid types in each slice is statistically analyzed. The optimization objective is to minimize the sum of the number of adjacent channel pairs with different amino acid types required by adjacent active channels on all slices. The optimal access path sequence for the robotic arm to 96 channels is derived.

[0111] The continuous segment division module: For each slice, the active channels in the active channel set are arranged according to the optimal access path sequence. The required amino acid types of adjacent active channels on the path are compared sequentially along the path direction. The active channels that are continuous on the path and have the same required amino acid types are divided into the same legal continuous segment. The nozzle change position is marked at the boundary of adjacent legal continuous segments.

[0112] Instruction generation module: For each valid continuous addition segment, calculate the addition volume based on the resin volume and amino acid parameters of the active channels within the valid continuous addition segment. Generate an AA addition instruction carrying the addition volume for the first active channel on the path within the valid continuous addition segment. Generate + addition instructions sequentially for subsequent active channels within the valid continuous addition segment. Generate a pipette head change instruction at the pipette head change position. Combine and output a complete sequence of lower-level machine control instructions in the order of preprocessing instruction block, slicing instruction block, and postprocessing instruction block.

[0113] It should be noted that the control command generation device for a 96-channel peptide synthesizer provided in this embodiment of the invention is used to execute all the process steps of the control command generation method for a 96-channel peptide synthesizer in the above embodiment 1. The working principles and beneficial effects of the two are one-to-one, so they will not be described again.

[0114] Finally, it should be noted that the above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for generating control commands for a 96-channel peptide synthesizer, characterized in that, include: S100: Receives peptide sequence set and process parameters, slices peptide sequence set according to amino acid position, identifies active channel set for each slice, counts the types of amino acids required for each active channel in the active channel set, and generates slice amino acid demand distribution matrix. S200: Based on the amino acid demand distribution matrix of the slice, the channel distribution of amino acid types in each slice is statistically analyzed. The optimization objective is to minimize the sum of the number of adjacent channel pairs with different amino acid types required by adjacent active channels on all slices. The optimal access path sequence for the robotic arm to 96 channels is derived. S300: For each slice, arrange the active channels in the active channel set according to the optimal access path sequence, compare the types of amino acids required by adjacent active channels along the path direction, divide the continuous active channels with the same types of required amino acids into the same legal continuation segment, and mark the nozzle change position at the boundary of adjacent legal continuation segments. S400: For each valid continuous addition segment, calculate the addition volume based on the resin volume and amino acid parameters of the active channels within the valid continuous addition segment. Generate an AA addition command carrying the addition volume for the first active channel on the path within the valid continuous addition segment. Generate + addition commands sequentially for the subsequent active channels within the valid continuous addition segment. Generate a pipette head change command at the pipette head change position. Combine and output a complete sequence of lower-level machine control commands in the order of preprocessing command block, slicing command block, and postprocessing command block.

2. The method for generating control commands for a 96-channel peptide synthesizer according to claim 1, characterized in that, In S100, the process parameters include: Channel resin amount; Target coupling equivalent; Molar mass of amino acids.

3. The method for generating control commands for a 96-channel peptide synthesizer according to claim 1, characterized in that, In S100, the slicing step includes: The total number of slices is determined by the number of amino acids in the longest sequence within the peptide sequence set. Each sequence is numbered sequentially starting from the anchoring end, and amino acids at the same number position in all sequences are grouped into the same slice; Channels with a sequence length shorter than the current slice number are not included in the active channel set of the current slice; Channels whose sequence length is equal to the current slice number are marked as exit channels.

4. The method for generating control commands for a 96-channel peptide synthesizer according to claim 1, characterized in that, In S100, the step of generating the sliced ​​amino acid demand distribution matrix includes: Construct a two-dimensional matrix with slice numbers as rows and amino acid types as columns; For each slice, iterate through the set of active channels and record the matrix elements corresponding to the types of amino acids required for each active channel as a list of channel numbers containing the current channel number; The matrix elements corresponding to amino acid types in the current slice that are not used by any active channels are set to empty.

5. The method for generating control commands for a 96-channel peptide synthesizer according to claim 1, characterized in that, In S200, the derivation steps of the optimal access path sequence include: The search space is defined by all permutations of the 96 channel numbers; For each candidate path sequence, traverse all slices, count the number of adjacent channel pairs with different amino acid types required by adjacent active channels along the path direction, and sum them to obtain the total number of pipette tip changes for the current candidate path sequence across all slices; The candidate path sequence with the minimum total number of gun head swaps is selected as the optimal access path sequence.

6. The method for generating control commands for a 96-channel peptide synthesizer according to claim 5, characterized in that, In S200, the derivation steps of the optimal access path sequence further include: The slice amino acid demand distribution matrix is ​​transformed into a channel similarity matrix. The elements of the channel similarity matrix are the number of slices in which the two channels have the same amino acid type in all slices. Using the channel similarity matrix as input, a greedy strategy is adopted to append the unvisited channel with the highest similarity to the end channel of the current path to the path in turn. When the similarity is the same, the channel with the smaller channel number is selected to obtain the initial path sequence. Swap the positions of any two channels in the initial path sequence. If the total number of times the nozzle is changed across all slices decreases after the swap, the swap is accepted. Repeat this process until the total number of times the nozzle is changed across all slices no longer decreases, and the optimal access path sequence is obtained.

7. The method for generating control commands for a 96-channel peptide synthesizer according to claim 1, characterized in that, In S300, the steps for dividing the legal continuation segment include: Arrange the set of active channels of the current slice according to the optimal access path sequence to obtain an ordered list of active channels of the current slice; Starting from the first channel in the ordered list of active channels, compare the types of amino acids required for the current channel with the next active channel on the path. If the amino acid types are the same, the next active channel will be assigned to the current valid continuation segment; If the amino acid type is different, the current legal addition segment ends and a new legal addition segment begins with the next active channel. After traversing the ordered list of active channels, we obtain all valid continuation segments and gun-head switching positions for the current slice.

8. The method for generating control commands for a 96-channel peptide synthesizer according to claim 2, characterized in that, In S400, the step of calculating the liquid addition volume includes: The total amount of liquid added in the AA liquid addition command is calculated by taking the sum of the resin volume of all active channels in the legal addition segment, the target coupling equivalent, and the molar mass of amino acids required by the active channels in the legal addition segment as inputs. Using the amount of resin in a single active channel within the legal continuous addition segment, the target coupling equivalent, and the molar mass of amino acids required for the active channel within the legal continuous addition segment as inputs, calculate the single addition volume of the + addition command. Write the total liquid volume into the liquid volume parameter of the AA liquid addition command, and write the single liquid volume into the liquid volume parameter of the + continue addition command.

9. The method for generating control commands for a 96-channel peptide synthesizer according to claim 3, characterized in that, In S400, the processing method for the exit channel includes: After all the amino acid addition instructions for the slice containing the exit channel are generated, an acetic anhydride addition instruction for the exit channel is generated to cap the free amino groups in the exit channel. After the endcapping is completed, the exit channel will be removed from the set of active channels for all subsequent slices; Subsequent slices will no longer generate any instructions for exiting the channel.

10. A control command generation device for a 96-channel peptide synthesizer, characterized in that, The apparatus is used to execute a method for generating control commands for a 96-channel peptide synthesizer according to any one of claims 1-9, the apparatus comprising: Demand Analysis Module: Receives peptide sequence set and process parameters, slices the peptide sequence set according to amino acid position, identifies active channel set for each slice, counts the types of amino acids required for each active channel in the active channel set, and generates slice amino acid demand distribution matrix; Path optimization module: Based on the slice amino acid demand distribution matrix, the channel distribution of amino acid types in each slice is statistically analyzed. The optimization objective is to minimize the sum of the number of adjacent channel pairs with different amino acid types required by adjacent active channels on all slices. The optimal access path sequence for the robotic arm to 96 channels is derived. The continuous segment division module: For each slice, the active channels in the active channel set are arranged according to the optimal access path sequence. The required amino acid types of adjacent active channels on the path are compared sequentially along the path direction. The active channels that are continuous on the path and have the same required amino acid types are divided into the same legal continuous segment. The nozzle change position is marked at the boundary of adjacent legal continuous segments. Instruction generation module: For each valid continuous addition segment, calculate the addition volume based on the resin volume and amino acid parameters of the active channels within the valid continuous addition segment. Generate an AA addition instruction carrying the addition volume for the first active channel on the path within the valid continuous addition segment. Generate + addition instructions sequentially for subsequent active channels within the valid continuous addition segment. Generate a pipette head change instruction at the pipette head change position. Combine and output a complete sequence of lower-level machine control instructions in the order of preprocessing instruction block, slicing instruction block, and postprocessing instruction block.

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