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

The development of molecular models with quantum-mechanical accuracy for predictive simulations of biomolecular systems has been a long-standing goal in the field of computational biophysics and biochemistry. As a first step toward a transferable force field for biomolecules entirely derived from "first-principles", we introduce a data-driven many-body energy (MB-nrg) potential energy function (PEF) for N-methylacetamide (NMA), a peptide bond capped by two methyl groups that is commonly used as a proxy for the protein backbone. The MB-nrg PEF is shown to accurately describe the energetics and structural properties of an isolated NMA molecule, including the normal modes of both cis and trans isomers and the energy variation along the isomerization path, as well as the multidimensional potential energy landscape of the NMA-H₂O dimer in the gas phase. Importantly, we show that the MB-nrg PEF is fully transferable, enabling molecular dynamics simulations of NMA in solution with quantum-mechanical accuracy. Comparisons with results obtained with a popular pairwise-additive force field for biomolecules and a classical polarizable PEF demonstrate the ability of the MB-nrg PEF to accurately represent many-body effects in NMA-H₂O interactions at both short and long distances, which is key to guaranteeing full transferability from the gas phase to the liquid phase.