Chimeric Non-Equilibrium Switching for Binding Free Energy Estimation

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Solution Overview

Problem

Existing methods for calculating binding free energy are inefficient and lack the ability to accurately simulate large and flexible molecules, leading to inaccurate results due to poor sampling of phase-space and long simulation times.

Innovation Solution

A non-equilibrium chimeric switching method is used to estimate free energy differences, incorporating enhanced sampling techniques and dual topology approaches to improve convergence and accuracy, allowing for faster and more efficient calculations.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If equilibrium-based methods are used to calculate binding free energy, then accuracy can be maintained, but computational time and resources increase significantly

Engineering Contradiction:

Improvebinding free energy accuracyVSAvoidsimulation time

Core Design Contradiction:

Measurement precisionVSLoss of time

Solution Approach 1:

The patent inverts the traditional equilibrium-based approach by using non-equilibrium switching methods. Instead of maintaining equilibrium throughout the transformation (which is computationally expensive), the method performs rapid non-equilibrium switches between end states and intermediate chimeric states, then uses fluctuation-dissipation theorems to extract accurate free energy differences from these non-equilibrium trajectories.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent replaces the mechanical equilibrium sampling approach with a statistical mechanics-based non-equilibrium method. By substituting the need for long equilibrium simulations with non-equilibrium measurements and theoretical relationships (fluctuation-dissipation theorems), the method achieves the same accuracy goal through a fundamentally different computational mechanism.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

2Reliability

If equilibrium-based methods are used to simulate large and flexible molecules, then thorough phase-space sampling can be achieved, but simulation times become excessively long

Engineering Contradiction:

Improvephase-space sampling qualityVSAvoidsimulation duration

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent introduces chimeric intermediate states that are pre-designed to bridge the phase-space gap between end states. These intermediate states are constructed beforehand with hybrid characteristics that facilitate better phase-space overlap, allowing the system to traverse conformational space more efficiently without requiring exhaustive equilibrium sampling.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent introduces chimeric intermediate molecular systems as mediators between the end states. These intermediates act as bridges that improve work overlap and facilitate phase-space sampling by providing transitional states with hybrid characteristics, reducing the computational burden of direct end-to-end transformations.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Productivity

If standard non-equilibrium switching is used, then computational speed improves, but convergence and work overlap deteriorate when end states have non-overlapping microstates

Engineering Contradiction:

Improvecalculation speedVSAvoidfree energy estimation accuracy

Core Design Contradiction:

ProductivityVSMeasurement precision

Solution Approach 1:

The patent applies local quality by designing chimeric intermediate states with spatially varying characteristics. Different regions of the chimera retain properties from different parent end states, creating localized zones of improved phase-space overlap. This allows rapid non-equilibrium switching to maintain both speed and convergence by having intermediate states that are locally optimized for different regions of phase-space.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20260066058A1Non-equilibrium chimeric switching for estimating free energy differences

Publication Date: 2026.03.05 SB TECH INC

AI summary

Methods, systems, and apparatus, including computer programs encoded on a computer storage medium, for estimating free energy differences via non-equilibrium chimeric switching. In one aspect, a method performed by one or more computers is described, the method including: receiving an input specifying a respective set of thermodynamic parameters of each of a first and second molecular system; processing the input to generate a Hamiltonian of an alchemical system including the first and second molecular systems; parametrizing the Hamiltonian with an alchemical progress parameter that implements an alchemical transformation between the first and second molecular systems; computing, via non-equilibrium switching along each alchemical path in the alchemical transformation, a respective free energy difference estimator between a corresponding pair of molecular systems connected by the alchemical path; and combining each of the free energy difference estimators to estimate a free energy difference between the first and second molecular systems.