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Collagen-integrin alpha2beta1 interacted polypeptide inhibitors and screening method thereof

A peptide inhibitor, collagen technology, applied in the direction of peptides, etc., can solve the problems of limited accuracy, time-consuming cost, fast calculation speed, etc.

Inactive Publication Date: 2014-07-30
TIANJIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, in the early stage, methods such as molecular docking with fast calculation speed but limited precision are used for preliminary screening, followed by MD simulation and other computationally intensive but more accurate methods for screening, and in the later stage, time-consuming and costly experiments are used. method validation

Method used

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  • Collagen-integrin alpha2beta1 interacted polypeptide inhibitors and screening method thereof
  • Collagen-integrin alpha2beta1 interacted polypeptide inhibitors and screening method thereof
  • Collagen-integrin alpha2beta1 interacted polypeptide inhibitors and screening method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0035] Example 1: Analysis of Collagen-Integrin α2β1 Interaction and Establishment of Peptide Inhibitor Library

[0036] First, the binding free energy of the α2A domain complex (PDB ID: 1DZI) in collagen-integrin α2β1 was calculated using the MM-PBSA method. Then, a free energy decomposition method based on MM-PBSA was used to analyze the molecular mechanism of the high affinity between collagen and α2A domain and to analyze the contribution of each residue in the collagen-α2A domain complex to the binding free energy. This identifies the key residues for their interactions. The criterion of <-2.5 kcal / mol was used to identify the residues that contributed more to the free energy, and it was found that only four residues, Y157, N154, S155 and R288, met the above requirements in α2A. Residue L220 contributes -1.9 kcal / mol to the free energy of the complex, which is slightly larger than -2.5 kcal / mol, but the contribution to the binding process follows Y157 and N154 so was als...

Embodiment 2

[0037] Embodiment 2: docking of polypeptide inhibitors and collagen fragments

[0038] Because a single residue has a strong affinity with collagen fragments, it does not necessarily mean that the polypeptide inhibitor composed of residues has a strong interaction with collagen fragments, so continue to use Vina to combine all the peptides in the peptide inhibitor library Inhibitors are sequentially docked with collagen fragments. Docking results showed that all peptide inhibitors could bind to collagen fragments, and the predicted binding free energy of all peptide inhibitors was between -7.2 and -3.7 kcal / mol. A total of 177 peptide inhibitors with binding free energy lower than -6.5 kcal / mol were selected.

[0039] In order to give full play to the affinity between key residues and collagen, it is necessary to search for peptide inhibitors whose docking conformation of key residues is consistent with that of the corresponding hot spot residues in α2A. Such peptides inhibit...

Embodiment 3

[0040] Example 3: Screening of polypeptide inhibitors and molecular dynamics simulation verification of their inhibitory effects

[0041] MD simulation is a very effective tool for studying protein dynamics. Protein fast internal motion, slow conformational change and folding process can all be studied using MD simulation. To further validate the collagen-peptide inhibitor interaction, not only its static structure (using molecular docking) but also its dynamic behavior should be studied. Therefore, MD simulation was used to study the dynamic information of the above-mentioned eight candidate peptide inhibitors binding to collagen fragments.

[0042] All MD simulations use the GROMACS 4.5.3 software package, select the G43a1 force field, and use the pdb2gmx command to convert the pdb coordinate structures of 8 candidate peptide inhibitors into the GROM structure dedicated to GROMACS; use the editconf command to convert the peptide inhibitors and collagen Placed at 10 x 7 x 5....

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Abstract

The invention discloses collagen-integrin alpha2beta1 interacted polypeptide inhibitors and a screening method thereof. The collagen-integrin alpha2beta1 interacted polypeptide inhibitors provided for the first time are LWWNSYY, LRWNSPY and LYWNSGY. According to a molecular mechanics-Poisson-Boltzmann solvent accessible surface area analysis method, the interaction between collagen short peptide and integrin alpha2beta1 on the surface of blood platelet is analyzed, so as to obtain a key residue with affinity interaction; therefore, a collagen-integrin alpha2beta1 interacted polypeptide inhibitor library can be constructed, the polypeptide inhibitors having high affinity to collagen can be obtained by screening polypeptides through molecular docking, root mean square deviation comparison and molecular dynamic simulation. Isothermal titration calorimetry experiments and blood platelet adsorption experiments proved that the obtained polypeptide inhibitors can inhibit the bonding between the collagen and integrin alpha2beta1, thus being potential high-efficiency thrombus inhibitors.

Description

technical field [0001] The invention relates to the construction of a rational design process of a polypeptide inhibitor of collagen-integrin α2β1 interaction and the acquisition of a new type of polypeptide inhibitor, which belongs to the field of computer simulation and protein interface behavior research in biotechnology. Background technique [0002] Thrombosis is a process in which vascular endothelial subtissues are exposed to plasma due to lesions on the vessel wall, which induces blood coagulation and causes vascular obstruction, leading to ischemic necrosis of organs and tissues, and cardiovascular diseases such as stroke and myocardial infarction . According to the statistics of the World Health Organization, the number of people who die from cardiovascular diseases is much higher than that from cancer every year, ranking first among all causes of death. Among them, the death and disability caused by myocardial infarction and cerebral infarction account for a larg...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06
Inventor 孙彦张麟张超
Owner TIANJIN UNIV
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