Feasibility of Combining Biomolecular Conformational Sampling Techniques for Molecular Dynamics Simulation

We assess the feasibility of combining two advanced molecular dynamics techniques for efficient biomolecular conformational sampling: the generalized ensemble method for enhancing conformational sampling in partial systems (GEPS), such as ALSD and REST2, which dynamically modulate atomic charges in selected regions, and the zero-multipole summation method (ZMM), which efficiently computes electrostatic interactions assuming local electrostatic neutrality. To address whether charge variation in GEPS violates the fundamental assumption of ZMM, we compared conformational ensembles obtained using GEPS combined with either ZMM or a conventional electrostatic calculation method. Our results demonstrate that GEPS and ZMM can be effectively combined without introducing systematic bias. Additionally, we identified a potential limitation of ZMM: in highly polarized systems, it may fail to capture long-range electrostatic repulsion, potentially leading to artifacts. These findings support the practical use of GEPS with ZMM for conformational sampling; however, caution is warranted when applying ZMM to systems with highly delocalized electrostatics.