We describe a strategy of integrating quantum mechanical (QM), hybrid quantum mechanical/molecular mechanical (QM/MM) and MM simulations to analyze the physical properties of a solid/water interface. This protocol involves using a correlated ab initio (CCSD(T)) method to first calibrate Density Functional Theory (DFT) as the QM approach, which is then used in QM/MM simulations to compute relevant free energy quantities at the solid/water interface using a meanfield approximation of Yang et al. that decouples QM and MM thermal fluctuations; gasphase QM/MM and periodic DFT calculations are used to determine the proper QM size in the QM/MM simulations. Finally, the QM/MM free energy results are compared with those obtained from MM simulations to directly calibrate the force field model for the solid/water interface. This protocol is illustrated by examining the orientations of an alkyl amine ligand at the gold/water interface, since the ligand conformation is expected to impact the chemical properties ( e.g. , charge) of the solid surface. DFT/MM and MM simulations using the INTERFACE force field lead to consistent results, suggesting that the effective gold/ligand interactions can be adequately described by a van der Waals model, while electrostatic and induction effects are largely quenched by solvation. The observed differencesmore »
Coupling Monte Carlo, variational implicit solvation, and binary levelset for simulations of biomolecular binding
We develop a hybrid approach that combines the Monte Carlo (MC)method, a variational implicitsolvent model (VISM), and a binary levelset method forthe simulation of biomolecular binding in an aqueous solvent. The solvation free energy for the biomolecular complex is estimated by minimizing the VISM freeenergy functional of all possible solute−solvent interfaces that are used as dielectric boundaries. This functional consists of the solute volumetric, solute−solvent interfacial, solute−solvent van der Waals interaction, and electrostatic free energy. A technique of shifting the dielectric boundary is used to accurately predict the electrostatic part of the solvation free energy.Minimizing such a functional in each MC move is made possible by our new and fast binary levelset method. This method is based on the approximation of surface area by the convolution of an indicator function with a compactly supported kernel and is implemented by simple flips of numerical grid cells locally around the solute−solvent interface. We apply our approach to the p53MDM2 system for which the two molecules are approximated by rigid bodies. Our efficient approach captures some of the poses before the final bound state. All atom molecular dynamics simulations with most of such poses quickly reach the final bound state.Our work is a more »
 Award ID(s):
 1913144
 Publication Date:
 NSFPAR ID:
 10288373
 Journal Name:
 Journal of chemical theory and computation
 Volume:
 17
 Page Range or eLocationID:
 24652478
 ISSN:
 15499618
 Sponsoring Org:
 National Science Foundation
More Like this


Highlevel quantum chemical computations have provided significant insight into the fundamental physical nature of noncovalent interactions. These studies have focused primarily on gasphase computations of small van der Waals dimers; however, these interactions frequently take place in complex chemical environments, such as proteins, solutions, or solids. To better understand how the chemical environment affects noncovalent interactions, we have undertaken a quantum chemical study of π– π interactions in an aqueous solution, as exemplified by Tshaped benzene dimers surrounded by 28 or 50 explicit water molecules. We report interaction energies (IEs) using secondorder Møller–Plesset perturbation theory, and we apply the intramolecular and functionalgroup partitioning extensions of symmetryadapted perturbation theory (ISAPT and FSAPT, respectively) to analyze how the solvent molecules tune the π– π interactions of the solute. For complexes containing neutral monomers, even 50 explicit waters (constituting a first and partial second solvation shell) change total SAPT IEs between the two solute molecules by only tenths of a kcal mol −1 , while significant changes of up to 3 kcal mol −1 of the electrostatic component are seen for the cationic pyridinium–benzene dimer. This difference between charged and neutral solutes is attributed to large nonadditive threebody interactions within solvated ioncontaining complexes. Overall,more »

Monte Carlo (MC) methods are important computational tools for molecular structure optimizations and predictions. When solvent effects are explicitly considered, MC methods become very expensive due to the large degree of freedom associated with the water molecules and mobile ions. Alternatively implicitsolvent MC can largely reduce the computational cost by applying a mean field approximation to solvent effects and meanwhile maintains the atomic detail of the target molecule. The two most popular implicitsolvent models are the PoissonBoltzmann (PB) model and the Generalized Born (GB) model in a way such that the GB model is an approximation to the PB model but is much faster in simulation time. In this work, we develop a machine learningbased implicitsolvent Monte Carlo (MLIMC) method by combining the advantages of both implicit solvent models in accuracy and efficiency. Specifically, the MLIMC method uses a fast and accurate PBbased machine learning (PBML) scheme to compute the electrostatic solvation free energy at each step. We validate our MLIMC method by using a benzenewater system and a proteinwater system. We show that the proposed MLIMC method has great advantages in speed and accuracy for molecular structure optimization and prediction.

We introduce a mathematical modeling framework for the conformational dynamics of charged molecules (i.e., solutes) in an aqueous solvent (i.e., water or salted water). The solvent is treated as an incompressible fluid, and its fluctuating motion is described by the Stokes equation with the Landau–Lifschitz stochastic stress. The motion of the solutesolvent interface (i.e., the dielectric boundary) is determined by the fluid velocity together with the balance of the viscous force,hydrostatic pressure, surface tension, solutesolvent van der Waals interaction force, and electrostatic force. The electrostatic interactions are described by the dielectric Poisson–Boltzmann theory.Within such a framework, we derive a generalized Rayleigh–Plesset equation, a nonlinear stochastic ordinary differential equation (SODE), for the radius of a spherical charged molecule, such as anion. The spherical average of the stochastic stress leads to a multiplicative noise. We design and test numerical methods for solving the SODE and use the equation, together with explicit solvent molecular dynamics simulations, to study the effective radius of a single ion. Potentially, our general modeling framework can be used to efficiently determine the solutesolvent interfacial structures and predict the free energies of more complex molecular systems.

Classical molecular dynamics simulations of the hydration thermodynamics, structure, and dynamics of water in hydration shells of charged buckminsterfullerenes are presented in this study. Charging of fullerenes leads to a structural transition in the hydration shell, accompanied by creation of a significant population of dangling O–H bonds pointing toward the solute. In contrast to the well accepted structure–function paradigm, this interfacial structural transition causes nearly no effect on either the dynamics of hydration water or on the solvation thermodynamics. Linear response to the solute charge is maintained despite significant structural changes in the hydration shell, and solvation thermodynamic potentials are nearly insensitive to the altering structure. Only solvation heat capacities, which are higher thermodynamic derivatives of the solvation free energy, indicate some sensitivity to the local hydration structure. We have separated the solvation thermodynamic potentials into direct solute–solvent interactions and restructuring of the hydration shell and analyzed the relative contributions of electrostatic and nonpolar interactions to the solvation thermodynamics.