Exploring Routes to Enhance the Calculation of Free Energy Differences via Nonequilibrium Work SQM/MM Switching Simulations by Using Hybrid Charge Intermediates Between MM and SQM Level of Theory or Non-linear Switching Schemes

Abstract

Nonequilibrium work switching simulations and Jarzynski’s equation are a reliable method to compute free energy differences, ΔAlow→high, between two levels of theory, such as a pure molecular mechanical (MM) and a quantum mechanical/molecular mechanical (QM/MM) description of a system of interest. Despite the inherent parallelism, the computational cost of this approach can quickly get very high. This is particularly true for systems where the core region, the part of the system to be described at different levels of theory, is embedded in an environment, such as explicit solvent water. We find that even for relatively simple solute–water systems, switching lengths of at least 5 ps are necessary to compute ΔAlow→high reliably. In this study, we investigate two approaches towards an affordable protocol, with emphasis on keeping the switching length well below 5 ps. Inserting a hybrid charge intermediate state with modified partial charges which resembles the charge distribution of the desired high level makes it possible to obtain reliable calculations with 2 ps switches. Attempts using step-wise linear switching paths, on the other hand, did not lead to improvement, i.e., faster convergence for all systems. To understand these findings, we analyzed the solutes’ properties as a function of partial charges used, the number of waters in direct contact with the solute, and studied the time needed for water molecules to reorient themselves upon a change in the solute’s charge distribution.

Using Neural Network Potentials to efficiently calculate indirect free energy estimates

“…56 Torsion profiles 57 2D constraint torsion profiles for hp2, hp7 and hp8 were generated using the geomeTRIC package[51].58geomeTRIC does not currently support ANI-2x, but it is possible to modify the OpenMM engine to generate 59 an ANI-2x system object and perform the torsion scan. In the Results & Discussion section, we reference 60 the torsion scan generated for hp7 in Schoeller et al[52]: note that the 𝜒 1 torsion angle in this work is 61 shifted by 180 degrees compared to the torsion scan shown there. Further details, input scripts and output…”