This is module is undergoing heavy development. None of the API calls are final. This software is provided without any guarantees of correctness, you will likely encounter bugs.

If you are interested in this code, please wait for the official release to use it. In the mean time, to stay informed of development progress you are encouraged to:


A Python framework for automated small molecule free energy driven design.

PERSES is a Python framework that uses OpenMM for GPU-accelerated molecular design driven by alchemical free energy calculations.


Perses performs relative free energy calculations using a single topology method. Single topology methods are those where the two ‘things’ that are being compared are done so by generating a single object whose parameters are perturbed between a representation of thing A to thing B. Perses supports perturbations between small molecules (for relative binding or relative hydration free energy calculations) and protein residues (resistance mutations).

Setting up and running a perses calculations involves three main stages.

Determining the atom-mapping of ligand A onto ligand B to work out the 2D topology of the single-topology alchemical object. Herein, alchemical topologies, systems, geometries etc. will be referred to as hybrid. This is handled by a ProposalEngine.

From this 2D hybrid topology, we then generate a 3D hybrid system. We use the input topology and coordinates for ligand A and the system and use RJMC to build in the atoms of ligand B. This is handled by a GeometryEngine.

With the hybrid system and hybrid topology, it’s possible to perform free energy calculations. Equilibrium methods such as REPEX and SAMS or non-equilibrium switching can be used. The method in which ligand A and ligand B are perturbed is handled by the LambdaProtocol, and sampled using samplers such as HybridSAMSSampler and HybridRepexSampler.

API Reference


  • Patrick B. Grinaway

  • Julie M. Behr

  • Hannah E. Bruce Macdonald

  • Dominic A. Rufa

  • Jaime Rodríguez-Guerra

  • Ivy Zhang

  • John D. Chodera

Indices and tables