US 2026/0290499 A1 · GENERATING BINDING FREE ENERGY UTILIZING INTELLIGENT RESTRAINTS AND LAMBDA STEPS FOR MOLECULAR DYNAMICS MODELS

Abstract

The present disclosure relates to systems, non-transitory computer-readable media, and methods for generating positional restraints and configuring lambda windows for execution within molecular dynamics simulation models. In particular, in one or more embodiments, the disclosed systems select restraint atoms based on geometry-conditioned loss metrics and apply positional restraints during staged lambda windows of an alchemical transformation to compute binding free energies between ligands and proteins. The disclosed systems generate candidate atoms, filter the candidate atoms based on angular criteria, and select restraint atom combinations using a loss function that penalizes angular variability and collinear geometries. In addition, in some embodiments, the disclosed systems configure and optimize lambda windows for annihilating nonbonded interactions using statistical free energy estimation techniques and variance-based selection. By coordinating restraint selection with lambda window scheduling, the disclosed systems improve stability and statistical reliability of molecular dynamics free energy calculations.

Claims20

Dependent claims

A computer-implemented method comprising:

generating, based on simulated binding interactions between a ligand and a protein, a plurality of candidate atoms for a molecular dynamics model;
generating a filtered set of candidate atoms by selecting a subset of candidate atoms from the plurality of candidate atoms based on angle metrics between the ligand and the protein for the subset of candidate atoms satisfying an angle metric threshold;
generating positional restraints between the ligand and the protein by selecting, from the filtered set of candidate atoms, restraint atoms based on a loss function that combines a measure of angular variability that penalizes angular variability with an angular conditioning factor that penalizes collinear geometry;
and
generating a binding free energy between the ligand and the protein by applying the positional restraints during lambda windows of the molecular dynamics model.

2 more elements

A non-transitory computer-readable medium storing instructions that, when executed by at least one processor, cause a computer system to:

generate, based on simulated binding interactions between a ligand and a protein, a plurality of candidate atoms for a molecular dynamics model;
generate a filtered set of candidate atoms by selecting a subset of candidate atoms from the plurality of candidate atoms based on angle metrics between the ligand and the protein for the subset of candidate atoms satisfying an angle metric threshold;
generate positional restraints between the ligand and the protein by selecting, from the filtered set of candidate atoms, restraint atoms based on a loss function that combines a measure of angular variability that penalizes angular variability with an angular conditioning factor that penalizes collinear geometry;
and
generate a binding free energy between the ligand and the protein by applying the positional restraints during lambda windows of the molecular dynamics model.

2 more elements

A system comprising:

at least one processor;
and
at least one non-transitory computer-readable storage medium storing instructions that, when executed by the at least one processor, cause the system to:
generate, based on simulated binding interactions between a ligand and a protein, a plurality of candidate atoms for a molecular dynamics model;
generate a filtered set of candidate atoms by selecting a subset of candidate atoms from the plurality of candidate atoms based on angle metrics between the ligand and the protein for the subset of candidate atoms satisfying an angle metric threshold;
generate positional restraints between the ligand and the protein by selecting, from the filtered set of candidate atoms, restraint atoms based on a loss function that combines a measure of angular variability that penalizes angular variability with an angular conditioning factor that penalizes collinear geometry;
and
generate a binding free energy between the ligand and the protein by applying the positional restraints during lambda windows of the molecular dynamics model.

5 more elements

Dependencies are inferred from the claim text.

Generating binding free energy utilizing intelligent restraints and lambda steps for molecular dynamics models

Life of this patent

Generating binding free energy utilizing intelligent restraints and lambda steps for molecular dynamics models

Life of this patent

Abstract

Claims20