Reliable simulations of complex biological processes whereby molecules undergo significant changes in their environment require robust force field models as well as efficient sampling methods to enable both the electronic and conformational degrees of freedom to accurately respond. Herein, we report the development and application of two novel methods for precise GPU-accelerated free energy simulation and analysis: the λ-SAMS and the 2D-vFEP(λ) methods. The λ-SAMS method uses MD to run the Gibbs-sampler along a fine-grid in space to produce a statistically optimal distribution. This accomplishes on-the-fly" what MBAR strives to achieve by re-weighting in a post-processing step. In this way λ-SAMS solves the phase space overlap problem dynamically, while at the same time collecting statistics on a fine grid that is ideal for TI’s integration requirements. The 2D-vFEP(λ) analysis, operating on the λ-SAMS dU/dλ data, uses a maximum likelihood approach to create an optimally smooth analytic 2D map of the (λ, dU/dλ) distribution that enables highly accurate TI. The new GPU-accelerated free energy sampling (λ-SAMS) and analysis (2D-vFEP(λ)) methods developed here will directly address a key barrier to progress for structure-based drug design (SBDD). Together, these methods unify existing thermodynamic integration (TI) and free energy perturbation (FEP) with multi-state Bennett acceptance ratio (MBAR) analysis, combining the advantages of each. Hence, λ-SAMS and 2D-vFEP(λ) will be of very high significance for improving the performance and precision of free energy estimation in lead refinement, and for a wide range of other applications outside the scope of the proposal. We will apply the λ-SAMS and 2D-vFEP(λ) methods on large scale solvation free energy and drug design datasets. The development of the GPU-accelerated free energy methods (λ-SAMS & 2D-vFEP(λ)) are highly significant for fast, high precision alchemical transformations with intense sampling requirements, and particularly for drug discovery applications.

New GPU-accelerated free energy simulation methods in AMBER

Macromolecular Chemistry: The Second Century

[Author Benefits](https://scimeetings.acs.org/?utm_source=pubs_content_marketing&utm_medium=website&utm_campaign=0320_MCF_NPI_Launch_Spring_Homepage&ref=pubs_content_marketing)

[How to use SciMeetings](https://storage.googleapis.com/dl.morressier.com/acs/SciMeetings-ACSSpring2020-HowToGuide_M3020-Final.pdf)

[Frequently Asked Questions](https://storage.googleapis.com/dl.morressier.com/acs/SciMtng_ACSNMSp2020_FAQ_M3120_Final.pdf)

ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.