Computation of Hydration Free Energies Using the Multiple Environment Single System Quantum Mechanical/Molecular Mechanical Method

Abstract

A recently-developed MESS-E-QM/MM method (multiple-environment single-system quantum mechanical molecular/mechanical calculations with a Roothaan-step extrapolation) is applied to the computation of hydration free energies for the blind SAMPL4 test set and for twelve small molecules. First, free energy simulations are performed with classical molecular mechanics force field using fixed-geometry solute molecules and explicit TIP3P solvent, then the non-Boltzmann-Bennett method is employed to compute the QM/MM correction (QM/MM-NBB) to the molecular mechanical hydration free energies. For the SAMPL4 set, MESS-E-QM/MM-NBB corrections to the hydration free energy can be obtained 2 or 3 orders of magnitude faster than fully converged QM/MM-NBB corrections, and, on average, the hydration free energies predicted with MESS-E-QM/MM-NBB fall within 0.10–0.20 kcal/mol of full-converged QM/MM-NBB results. Out of five density functionals (BLYP, B3LYP, PBE0, M06-2X, and ωB97X-D), the BLYP functional is found to be most compatible with the TIP3P solvent model and yields the most accurate hydration free energies against experimental values for solute molecules included in this study.

Quantum Chemical Analyses of BH4− and BH3OH− Hydride Transfers to CO2 in Aqueous Solution with Potentials of Mean Force

“…These reaction pathways all involve explicit solvation and an Na + counteri on and were obtained with G-SSNEB calculations in previous work (Ref. [14]). www.chemphyschem.org from PMF modeling is lower relative to the G-SSNEB pathway.…”

“…[9,11] More robustc omputationalt reatments such as metadynamics [12] or transition path sampling [13] explicitly models olvent environments and can more physically identify complete reaction mechanisms through extended molecular dynamics simulations, but these approaches bring far higher computational costs. The use of semi-empirical or QM/MM methods can decrease computational expense, [14] but thesea pproaches may also have lower accuracy and be less transferrable than ab initio (or Born-Oppenheimer) molecular dynamics simulations. [15] In the presents tudy,w em odeled solvent-phase free energies along specific hydride transfer pathways with umbrella sampling simulationsu sing Kohn-Sham density functional theory.…”

An efficient protocol for obtaining accurate hydration free energies using quantum chemistry and reweighting from molecular dynamics simulations

“…König et al [2016] This approach approximates a full QM/MM calculation by approximating the effect of the classical solvent molecules as a perturbation to the gas phase wave function, instead of treating it in a fully self consistent manner. This requires constraining both the solute and solvent molecules to rigid bodies, however it increases the speed of the QM/MM energy calculations by several orders of magnitude relative to the regular procedure.…”

“…This result is consistent with other QM/MM explicit solvent HFE studies. König et al [2016]; Shaw et al [2010] Water models that explicitly account for polarization and charge-penetration effects may mitigate these issues, and studying their effectiveness will be the subject of followup work.…”

Isotropic periodic sum for multipole interactions and a vector relation for calculation of the Cartesian multipole tensor

“…It is recognized that multipoles have their advantages in describing molecular interactions. [35][36][37][38][39][40][41][42][43][44] They are increasingly employed in force field development, such as the AMOEBA force field 45,46 and the sticky water model. 47 Even though multipole interactions decay faster than chargecharge interactions, the large number of multipole interaction components makes a reduction of interaction pairs highly desirable in simulation.…”