A computationally efficient subspace harmonic relaxation algorithm for coarse-graining of molecular systems with nearly exact thermodynamic consistency

Abstract

In a recent paper [Pimentel and Mandelshtam, J. Chem. Phys. 162, 214101 (2025)], a novel approach for the rigidification of a molecular cluster was proposed, in which, starting with an all-atom (AA) potential, a coarse-grained (CG) potential for the associated cluster of rigid monomers was constructed directly. The method is based on using the harmonic approximation for the fast intramolecular degrees of freedom. While conceptually primitive, the resulting CG model turned out to be surprisingly accurate for selected water and ammonia clusters. However, as originally formulated, a single evaluation of the CG potential turned out to be much more expensive than the evaluation of the AA potential, since the former required a subspace minimization followed by a subspace normal mode calculation. In this communication, we formulate the approach more broadly, making it applicable, e.g., to coarse-graining a large protein. We also introduce key algorithmic improvements, reducing the cost of the subspace minimization and normal mode calculation. Combined with the fact that the CG simulation requires roughly an order of magnitude fewer Monte Carlo steps to reach similar statistical accuracy for selected observables compared to the AA model, the overall computational cost becomes comparable. These improvements are demonstrated on a water cluster.