D-Protein Ligand Design via Mirror Inversion
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Solution Overview
Problem
Current methods for designing synthetic proteins and polypeptides with D-amino acids that bind to target proteins built of L-amino acids are limited by the size of the target and the ability to construct the target epitope in a D-protein format, making it challenging to develop effective prophylactic, therapeutic, or diagnostic agents with high specificity and stability.
Innovation Solution
The development of in silico computing methodologies that design D-ligands capable of binding to L-targets, allowing for the selection and optimization of protein sequences without size limitations, using mirror inversion and scaffold matching techniques to generate D-ligands that can interact with L-targets, thereby overcoming the limitations of existing technologies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If current methods for designing D-protein ligands are used, then the design process is constrained by target size limitations, but the ability to bind to L-targets with high specificity is compromised
Solution Approach 1:
The patent applies mirror image inversion to create D-protein ligands that bind to L-targets. By inverting the chirality of the protein scaffold and binding interface, the invention enables D-proteins to recognize and bind to natural L-amino acid targets with high specificity, overcoming the conventional limitation that D-proteins cannot bind to L-protein targets effectively
Solution Approach 2:
The invention changes the fundamental parameter of amino acid chirality from L to D configuration in the protein scaffold while maintaining the binding interface geometry through computational design. This parameter change allows the D-protein to adapt to targets of various sizes without compromising binding specificity, as the mirror-image structure preserves the essential stereocomplementary interactions
2Stability of the object's composition
If D-amino acid containing proteins are designed to improve stability and half-life, then proteolytic resistance is enhanced, but immunogenicity may increase
Solution Approach 1:
The patent employs local quality by selectively placing D-amino acids in specific regions of the protein scaffold rather than uniformly throughout. The core scaffold and binding interface are designed with D-amino acids to provide proteolytic resistance, while surface residues are optimized to minimize immunogenic recognition by the human immune system, thus achieving both stability and reduced immunogenicity
3Reliability
If computational design methods are used to optimize binding interactions, then binding affinity is improved, but the complexity of the design process increases
Solution Approach 1:
The computational design process is segmented into distinct modules: scaffold selection, mirror image generation, binding interface optimization, and stability enhancement. Each module addresses a specific aspect of the design problem independently, allowing for systematic optimization of binding affinity without overwhelming complexity. The segmented approach enables iterative refinement of each component while maintaining overall design coherence
Data Source
AI summary
A method of designing a D-polypeptide that binds with an L-target protein can include: identifying a polypeptide target having L-chirality; determining hotspot amino acids of a polypeptide ligand having L-chirality that have binding interactions with the L-target protein; determining transformations of side chains of the hotspot amino acids that retain the binding interactions with the target; generating inversed hotspot amino acids with chirality opposite to the one of the target; identifying a polypeptide having inverse chirality from the target protein, on which a combination of inversed hotspot amino-acid can be grafted without significantly changing their interactions with the target. The designed ligands can be processed and converted to D-ligands that bind with the L-target protein.