Preprocessing Binding Free Energy Calculation with Constrained Sampling
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Solution Overview
Problem
Existing methods for calculating binding free energy, such as the alchemical pathway calculation method, face challenges in maintaining accurate predictions when the binding state between substances easily changes, leading to decreased calculation accuracy due to shifts in the binding state during preprocessing.
Innovation Solution
A preprocessing method that constrains the binding state of the second substance to a predetermined state and then releases the constraint to obtain the binding structure, thereby stabilizing the sampling volume and improving calculation accuracy, even when the binding state changes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If the binding state is allowed to change freely during sampling, then the system maintains natural flexibility and adaptability, but the calculation accuracy of binding free energy deteriorates when the binding state easily changes
Solution Approach 1:
The patent applies preliminary action by performing a preprocessing step before the main binding free energy calculation. In this preprocessing stage, the binding state is constrained to a predetermined state to obtain an initial structure that serves as a stable starting point. This preliminary constraint prevents unwanted binding state changes during the subsequent sampling process, thereby ensuring calculation accuracy while still allowing natural flexibility once the constraint is released.
Solution Approach 2:
The calculation process is segmented into distinct stages: a preprocessing stage with binding state constraints to establish a stable initial structure, followed by a main calculation stage where constraints are released to allow natural binding state flexibility. This segmentation allows each stage to optimize for its specific purpose - stability during structure preparation and flexibility during energy calculation.
2Measurement precision
If constraints are applied to maintain binding state, then calculation accuracy is improved, but the system loses natural flexibility and requires additional preprocessing steps
Solution Approach 1:
The constraint application is implemented as a preliminary action in the preprocessing stage, which is a standard and well-defined procedure in molecular simulations. By confining the binding state constraint to this initial preparation phase, the patent minimizes the complexity impact while achieving the goal of improved calculation accuracy in the main sampling stage.
3Adaptability or versatility
If binding state constraints are released immediately, then natural binding flexibility is restored, but the sampling volume shifts and calculation accuracy deteriorates
Solution Approach 1:
The patent uses preliminary action to establish a stable initial structure with constrained binding state before releasing the constraints. This preliminary structuring ensures that when flexibility is restored, the system starts from a well-defined configuration, preventing unwanted shifts in sampling volume and maintaining calculation accuracy throughout the flexible sampling process.
Data Source
AI summary
A method is performed by a computer for a preprocessing for calculating binding free energy between a first substance and a second substance. The method includes: obtaining a binding structure of the first substance and the second substance under a condition where the second substance is constrained such that a binding state of the second substance to the first substance is maintained in a predetermined state; and then, based on the obtained binding structure, obtaining the binding structure under a condition where the second substance is not constrained.