Por Chris Oostenbrink (University of Natural Resources and Life Sciences, Wien, Austria).

Physically relevant free-energy differences can be calculated from simulations of unphysical reference states. Over the years, we have successfully applied the one-step perturbation method by the judicious design of reference states. To ensure overlap between the reference state and the end states enveloping distribution sampling (EDS) was developed over a decade ago [1]. Here, the reference state is constructed from the end states directly, potentially maximizing the overlap in sampling. By accelerating the EDS potential [2] improved sampling of the end-states becomes feasible. Various applications in drug-design settings [3] show that the accelerated EDS approach (A-EDS) can also enhance the sampling of orthogonal degrees of freedom [4] and may furthermore be used as a chemostat. This opens the way to applications in virtual screening or the sampling of water molecules in the active site of protein-ligand complexes.

• [1] C.D. Christ, and W.F. van Gunsteren, Enveloping distribution sampling: a method to calculate free energy differences from a single simulation. J. Chem. Phys. (2007) 184110.
• [2] J.W. Perthold and C. Oostenbrink. Accelerated enveloping distribution sampling: enabling sampling of multiple end-states while preserving local energy minima. J. Phys. Chem. B, 122 (2018) 5030 – 5037. doi: 10.1021/acs.jpcb.8b02725
• [3] J.W. Perthold, D. Petrov, C. Oostenbrink. Towards Automated Free Energy Calculation with Accelerated Enveloping Distribution Sampling (AEDS). J. Chem. Inf. Model. 60 (2020) 5395 – 5406. doi: 10.1021/acs.jcim.0c00456/
• [4] O. Gracia Carmona and C. Oostenbrink. Accelerated Enveloping Distribution Sampling (AEDS) allows for efficient sampling of orthogonal degrees of freedom. J. Chem. Inf. Model. 63 (2023) 197 – 207. doi: 10.1021/acs.jcim.2c01272

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