The Binding Affinity Calculator (BAC), developed by the team of Prof Peter Coveney at University College London (UK), is a workflow tool that runs and analyses simulations designed to assess how well drugs bind to their target proteins and the impact of changes to those proteins. It is a collection of scripts which wrap around common molecular dynamics codes to facilitate free energy calculations. Use of ensemble simulations to robust, accurate and precise free energy computations from both alchemical and end-point analysis methodologies.
BAC or Binding Affinity Calculator encompasses two highly related methodologies. These two methodologies are Thermodynamic Integration with Enhanced Sampling (TIES) and Enhanced Sampling of Molecular dynamics with Approximation of Continuum Solvent (ESMACS). Centrally both these methods make use of ensembles of molecular dynamics (MD) simulations to control for the inherently chaotic nature of the trajectories MD produces. The trajectories collected can be used to calculate the binding affinity of ligand and protein. These affinities are calculated as a free energy of binding which is a critical quantity relevant in drug design and personalized medicine. The free energy difference between two states is an important quantity in biology, because it determines the ensemble at equilibrium. The binding free energy of an inhibitor often correlates to its effectiveness. As such the accurate prediction of binding free energies has been a longstanding goal of computational methods. The two protocols are complementary in that ESMACS is an absolute free energy method for the ranking of binding affinities for highly diverse compounds, whereas TIES is a relative free energy method for the estimation of free energy differences for pairs of similar (congeneric) compounds and/or mutated protein sequences.
TIES aims to alleviate many of the bottlenecks in relative binding free energy calculations however, due to the complexity and large computational cost of running these calculations TIES is targeted at expert users experienced in alchemical free energy calculation. We provide tutorials on how to run calculations using TIES via our online documentation for the project. BAC is a fairly complex tool to use, so at the moment the development team at UCL have made it available as part of consulting services or research collaborations.
HPC usage and parallel performance
- Wan S et al. 2020, Rapid, accurate, precise and reproducible ligand–protein binding free energy prediction. DOI
- Zasada SJ et al. 2020, Large-scale binding affinity calculations on commodity compute clouds. DOI
- Sadiq SK et al. 2008, Automated Molecular Simulation Based Binding Affinity Calculator for Ligand-Bound HIV-1 Proteases. DOI