Coarse-Grained Free Energy Surface with Implicit Nuclear Quantum Effects: Benzene Clusters.

Starting with an all-atom potential energy surface, we apply a recently introduced intramolecular coarse-graining framework to incorporate nuclear quantum effects in molecular cluster simulations without resorting to path-integral methods. As in previous work [ J. Chem. Phys. 2025, 163, 131101], the configuration space is partitioned into slow intermolecular degrees of freedom and fast intramolecular vibrational modes. Here, the latter are treated quantum mechanically within the local harmonic approximation, allowing zero-point energies and finite-temperature vibrational free energy contributions to be included. The resulting temperature-dependent effective free energy surface is sampled using classical Monte Carlo, yielding equilibrium properties that account for nuclear quantum effects while sampling a lower-dimensional configurational space. The approach is applicable to systems in which the slow intermolecular modes are well-described classically. We use the method to assess the nuclear quantum and isotope effects in a benzene cluster and demonstrate that, although very small, they can be quantified.