Microprotein Chignolin Backbone for Stable Polypeptide Libraries
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Solution Overview
Problem
Current molecular libraries for polypeptides face challenges in achieving a balance between molecular weight, stability, and production cost, with existing protein backbone-type libraries being either too large and costly or requiring complex cyclization processes, while short-chain peptide libraries lack stability and affinity.
Innovation Solution
A molecular library of polypeptides using the backbone structure of the microprotein chignolin, which spontaneously forms a stable three-dimensional structure, allowing for the identification of novel functional molecules with reduced molecular weight and simplified synthesis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If a protein backbone-type library is constructed using natural proteins or artificial proteins as scaffolds, then the molecules have stable three-dimensional structures and can be screened for novel functions, but the molecular size becomes relatively enormous leading to high production costs and reduced storage stability
Solution Approach 1:
The invention extracts and utilizes only the essential backbone structural features required for stability (such as beta-turn formations in 7-10 residue peptides) while removing the unnecessary bulk of larger protein scaffolds. This allows achieving structural stability with minimal molecular size, resolving the contradiction between stability and molecular weight.
Solution Approach 2:
The invention changes the key parameter of peptide length from the conventional 7-10 residues to a optimized range that maintains structural stability while minimizing molecular weight. By carefully controlling the number of residues and their sequence composition, the patent achieves stable beta-turn structures with reduced molecular size, thereby lowering production costs and improving storage stability.
2Ease of manufacture
If short-chain peptides of 7 to 10 residues are randomized to create a molecular library, then the library is relatively easy to construct and screen with low production costs, but the molecules lack stable three-dimensional structures and have reduced affinity
Solution Approach 1:
The invention applies local quality by introducing specific stabilizing structural motifs (beta-turns) at critical positions within the short peptide sequence. Rather than randomizing the entire sequence, the patent maintains specific structural features locally that confer stability, while allowing diversity in other regions. This enables short peptides to form stable three-dimensional structures without compromising ease of library construction.
3Stability of the object's composition
If cyclic oligopeptide backbones are used to create stable structures with small molecular weight, then the molecules have enhanced stability, but the cyclization requires introduction of functional groups and complicated chemical reaction operations
Solution Approach 1:
The invention adopts a disposable linear peptide backbone design that achieves stability through intrinsic structural motifs (beta-turns) rather than requiring permanent cyclic modifications. This approach avoids the need for complex cyclization chemistry, functional group introductions, and purification steps, thereby simplifying synthesis while maintaining stability. The linear structure can be directly synthesized and used without additional modification steps.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Enables the preparation of novel functional molecules with high binding affinity and stability at a lower molecular weight than conventional libraries, reducing production costs and avoiding complex cyclization processes, while maintaining structural integrity.
Implementation Method 1
the backbone structure of a microprotein such as chignolin, which spontaneously forms a stable three-dimensional structure
Data Source
Figure 1
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Figure 3(A)~3(E)
AI summary
Disclosed is a molecular library comprising a group of a plurality of molecules, wherein each member of the library is a polypeptide having a randomized sequence moiety and a microprotein moiety. The microprotein is a protein comprising an amino acid sequence of 30 or less amino acid residues having the ability to form a particular conformation by spontaneous folding in a solution and is, for example, chignolin comprising the amino acid sequence represented by SEQ ID NO: 1. Also, disclosed is a method for identifying a novel functional molecule using the library of the present invention.