TY - JOUR

T1 - 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

AU - Schöller, Andreas

AU - Woodcock, H. Lee

AU - Boresch, Stefan

N1 - Accession Number: WOS:000997693600001
PubMed ID: 37241747

PY - 2023/5

Y1 - 2023/5

N2 - Non-equilibrium work switching simulations and Jarzynski’s equation are a reliable method for computing free energy differences, (Formula presented.), 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 (Formula presented.) 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.

AB - Non-equilibrium work switching simulations and Jarzynski’s equation are a reliable method for computing free energy differences, (Formula presented.), 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 (Formula presented.) 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.

KW - free energy

KW - indirect thermodynamic cycle

KW - non-equilibrium simulation

UR - http://www.scopus.com/inward/record.url?scp=85160372811&partnerID=8YFLogxK

U2 - 10.3390/molecules28104006

DO - 10.3390/molecules28104006

M3 - Article

C2 - 37241747

AN - SCOPUS:85160372811

VL - 28

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 10

M1 - 4006

ER -