Grand Canonical Monte Carlo and Deep Learning Assisted Enhanced Sampling to Characterize the Distribution of Mg2+ and Influence of the Drude Polarizable Force Field on the Stability of Folded States of the Twister Ribozyme

Molecular Dynamics (MD) simulations are crucial for understanding the structural and dynamical behavior of biomolecular systems including the impact of their environment. However, there is a gap in timescale of these simulations and that of real-world experiments. To address this problem, various enhanced simulation methods have been developed. Additionally, there has been a significant advancement of the force fields used for simulations associated with the explicit treatment of electronic polarizability. In this study, we apply oscillating chemical potential grand canonical Monte Carlo and machine learning methods to determine reaction coordinates combined with metadynamics simulations to explore the role of Mg2+ distribution and electronic polarizability in the context of the classical Drude oscillator polarizable force field on the stability of the Twister ribozyme. The introduction of electronic polarizability along with details of the distribution of Mg2+ significantly stabilize the simulations with respect to sampling the crystallographic conformation. The introduction of electronic polarizability leads to increased stability over that obtained with the additive CHARMM36 FF reported in a previous study, allowing for a wider range of ions distribution to stabilize Twister. Specific interactions contributing to stabilization are identified included both those observed in the crystal structures and additional experimentally unobserved interactions. Interactions of Mg2+ with the bases are indicated to make important contributions to stabilization. Notably, the presence of specific interactions between the Mg2+ ions and bases or the non-bridging phosphate oxygens (NBPO), lead to enhanced dipole moments of all three moieties. Mg2+-NPBO interactions led to enhanced dipoles of the phosphates but, interestingly, not in all of the participating ions. The present results further indicate the importance of electronic polarizability in stabilizing RNA in molecular simulations and the complicated nature of the relationship of Mg2+-RNA interactions with polarization response of the bases and phosphates.