Toward Data-Driven Many-Body Simulations of Biomolecules in Solution: N-Methyl Acetamide as a Proxy for the Protein Backbone

RH Zhou and M Riera and F Paesani, JOURNAL OF CHEMICAL THEORY AND COMPUTATION, 19, 4308-4321 (2023).

DOI: 10.1021/acs.jctc.3c00271

The development of molecular models with quantum-mechanicalaccuracyfor predictive simulations of biomolecular systems has been a long- standinggoal in the field of computational biophysics and biochemistry. Asa first step toward a transferable force field for biomolecules entirelyderived from "first-principles", we introduce a data-drivenmany- body energy (MB-nrg) potential energy function (PEF) for N-methylacetamide (NMA), a peptide bond capped by two methylgroups that is commonly used as a proxy for the protein backbone.The MB-nrg PEF is shown to accurately describe the energetics andstructural properties of an isolated NMA molecule, including the normalmodes of both cis and trans isomersand the energy variation along the isomerization path, as well asthe multidimensional potential energy landscape of the NMA-H2O dimer in the gas phase. Importantly, we show that the MB-nrgPEF is fully transferable, enabling molecular dynamics simulationsof NMA in solution with quantum-mechanical accuracy. Comparisons withresults obtained with a popular pairwise-additive force field forbiomolecules and a classical polarizable PEF demonstrate the abilityof the MB-nrg PEF to accurately represent many-body effects in NMA-H2O interactions at both short and long distances, which iskey to guaranteeing full transferability from the gas phase to theliquid phase.

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