Generation of conformational ensembles of small molecules via Surrogate Model-Assisted Molecular Dynamics

24 November 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


The accurate prediction of thermodynamic properties is crucial in various fields such as drug discovery and materials design. This task relies on sampling from the underlying Boltzmann distribution, which is challenging using conventional approaches such as simulations. In this work, we introduce Surrogate Model-Assisted Molecular Dynamics (SMA-MD), a new procedure to sample the equilibrium ensemble of molecules. First, SMA-MD leverages Deep Generative Models to enhance the sampling of slow degrees of freedom. Subsequently, the generated ensemble undergoes statistical reweighting, followed by short simulations. Our empirical results show that SMA-MD generates more diverse and lower energy ensembles than conventional Molecular Dynamics simulations. Furthermore, we showcase the application of SMA-MD for the computation of thermodynamical properties by estimating implicit solvation free energies.


Equilibrium sampling
Generative models
Boltzmann distribution
Molecular conformation generation
Molecular Dynamics
Property prediction


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Comment number 1, Chris Neale: Nov 29, 2023, 05:00

how does this method propose to address Boltzmann ensembles with explicit solvent, whose water-water potential energies may drown out the easy potential energy-based reweighting?