Exploring Routes to Enhance the Calculation of Free Energy Differences via Non-Equilibrium Work SQM/MM Switching Simulations Using Hybrid Charge Intermediates between MM and SQM Levels of Theory or Non-Linear Switching Schemes

Abstract

Non-equilibrium work switching simulations and Jarzynski’s equation are a reliable method for computing 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 become 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 an 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., a faster convergence for all systems. To understand these findings, we analyzed the solutes’ properties as a function of the partial charges used and the number of water molecules 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.

Accurate and Efficient Multilevel Free Energy Simulations with Neural Network-Assisted Enhanced Sampling

“…The performance of our neural network-assisted approach, which first learns an optimal latent space and then constructs an intermediate distribution to facilitate the convergence of free energy correction, can be further enhanced with more sophisticated molecular features, such as those representing the nearby solvent distributions. ,, In fact, we note that the two levels of theory can differ significantly in not only structural distributions but also electronic properties, such as charge distributions, , which lead to different interactions with the environment. For such cases, including the environmental features in the training of the latent space is expected to be particularly important.…”

“…In some cases, the intermediate model differs only from the low level in terms of charge distributions. , Alternatively, when ensembles at the two levels of theory show substantial structural differences, the intermediate model can be derived by performing biased simulations at the low level toward configurations favored by the high level of theory. Such a staged approach is particularly attractive because the biased simulations required to establish the intermediate model can follow collective coordinates that compactly describe the “problematic” DOFs, rather than specify the latter individually, as required in methods that explicitly modify the low-level potential function.…”

Reweighting from Molecular Mechanics Force Fields to the ANI-2x Neural Network Potential

“…does not currently support , but it is possible to modify the engine to generate an system object and perform the torsion scan. In the Results and Discussion section, we reference the torsion scan generated for hp 7 in Schoeller et al: note that the χ 1 torsion angle in this work is shifted by 180° compared to the torsion scan shown there. Further details, input scripts, and output data can be found at .…”

Host Dynamics under General-Purpose Force Fields

“…Practically, no significant difference exists between host dynamics produced by GAFF and GAFF2, and picking either option seems fine, although energetically, GAFF is slightly better than GAFF2. However, it should be noted that when bond-length-related observables or in situations where accurate energetics are crucial (e.g., reweighting between force field descriptions and ab initio levels) [ 58 , 59 , 60 , 61 ], the pre-fitted GAFF derivatives could be non-satisfactory and refitted force fields could be necessary.…”