Toward Chemical Accuracy in Biomolecular Simulations through Data-Driven Many-Body Potentials: II. Polyalanine in Water

Accurate modeling of biomolecular systems under physiological conditions requires potential energy functions (PEFs) that reliably capture many‑body interactions both within the biomolecule and between the biomolecule and the surrounding aqueous environment. Here, we extend the intramolecular MB‑nrg framework, previously developed for gas‑phase molecules, to simulate biomolecules in solution, using polyalanine in water as a proof‑of‑concept system. By integrating machine-learned terms trained on DLPNO-CCSD(T) reference data with physics‑based expressions within the many‑body expansion of the energy, we develop an MB‑nrg PEF that simultaneously accounts for intramolecular interactions within polyalanine chains and intermolecular polyalanine--water interactions that shape the structure and dynamics of polyalanine in solution. The MB-nrg PEF adopts a unified, modular architecture spanning both polyalanine and water. We evaluate the performance of the MB-nrg PEF by comparing interaction energies, conformational free‑energy surfaces, and hydration properties against DLPNO‑CCSD(T) reference data and empirical force fields. These analyses demonstrate the transferability of the MB‑nrg formalism from the gas phase to aqueous environments for polypeptides, offering a scalable route toward chemically accurate biomolecular simulations.