We describe a novel two-step approach for combining cloud-mounted interactive molecular dynamics in virtual reality (iMD-VR) with free energy sampling (FES) approaches to quantitatively explore the dynamics of biological processes at the molecular level. The combined approach we refer to as the iMD-VR-FES protocol. Stage one involves using a state-of-the-art iMD-VR framework to quickly sample a diverse range of protein-ligand unbinding pathways, benefitting from the sophistication of human spatial and chemical intuition. Stage two involves using the iMD-VR-sampled pathways as initial guesses for defining a path-based reaction coordinate from which we can obtain a corresponding free energy profile using FES methods. To investigate the performance of the method, we apply iMR-VR-FES to investigate the unbinding of a benzamidine ligand from a trypsin protein. Unbinding free energies calculated using iMD-VR-FES show good internal consistency, and broadly agree with previous literature values. Moreover, the resulting free energy profiles can distinguish energetic differences corresponding to various protein-ligand conformations (e.g., helping to identifying favorable vs. unfavorable pathways) and also enable identification of metastable states along the unbinding pathways. The two-step iMD-VR-FES approach offers an intuitive way for researchers to test various hypotheses of dynamical and conformational change, in order to quickly obtain both qualitative and quantitative insight.
Virtual reality sampled pathways guide free energy calculation of protein-ligand binding (supplementary text)
Virtual reality sampled pathways guide free energy calculation of protein-ligand binding (supplementary files)