Lambda-ABF-OPES: Faster Convergence with High Accuracy in Alchemical Free Energy Calculations.

Predicting the binding affinity between small molecules and target macromolecules while combining both speed and accuracy is a cornerstone of modern computational drug discovery, which is critical for accelerating therapeutic development. Despite recent progress in molecular dynamics (MD) simulations, such as advanced polarizable force fields and enhanced sampling techniques, estimating absolute binding free energies (ABFEs) remains computationally challenging. To overcome these difficulties, we introduce a highly efficient hybrid methodology that couples the Lambda-adaptive biasing force (Lambda-ABF) scheme with on-the-fly probability enhanced sampling (OPES).

Unexpected Single-Ligand Occupancy and Negative Cooperativity in the SARS-CoV-2 Main Protease.

Many homodimeric enzymes tune their functions by exploiting either negative or positive cooperativity between subunits. In the SARS-CoV-2 Main protease (Mpro) homodimer, the latter has been suggested by symmetry in most of the 500 reported protease/ligand complex structures solved by macromolecular crystallography (MX). Here we apply the latter to both covalent and noncovalent ligands in complex with Mpro.

OneOPES, a Combined Enhanced Sampling Method to Rule Them All.

Enhanced sampling techniques have revolutionized molecular dynamics (MD) simulations, enabling the study of rare events and the calculation of free energy differences in complex systems. One of the main families of enhanced sampling techniques uses physical degrees of freedom called collective variables (CVs) to accelerate a system's dynamics and recover the original system's statistics. However, encoding all the relevant degrees of freedom in a limited number of CVs is challenging, particularly in large biophysical systems.

Rare Event Kinetics from Adaptive Bias Enhanced Sampling.

We introduce a novel enhanced sampling approach named on-the-fly probability enhanced sampling (OPES) flooding for calculating the kinetics of rare events from atomistic molecular dynamics simulation. This method is derived from the OPES approach [Invernizzi and Parrinello, 7, 2731-2736], which has been recently developed for calculating converged free energy surfaces for complex systems. In this paper, we describe the theoretical details of the OPES flooding technique and demonstrate the application on three systems of increasing complexity: barrier crossing in a two-dimensional double-well potential, conformational transition in the alanine dipeptide in the gas phase, and the folding and unfolding of the chignolin polypeptide in an aqueous environment.

Water regulates the residence time of Benzamidine in Trypsin.

The process of ligand-protein unbinding is crucial in biophysics. Water is an essential part of any biological system and yet, many aspects of its role remain elusive. Here, we simulate with state-of-the-art enhanced sampling techniques the binding of Benzamidine to Trypsin which is a much studied and paradigmatic ligand-protein system.

Charge Gradients around Dendritic Voids Cause Nanoscale Inhomogeneities in Liquid Water.

Water is the matrix of life and serves as a solvent for numerous physical and chemical processes. The origins of the nature of inhomogeneities that exist in liquid water and the time scales over which they occur remains an open question. Here, we report femtosecond elastic second harmonic scattering (fs-ESHS) of liquid water in comparison to an isotropic liquid (CCl) and show that water is indeed a nonuniform liquid.

Water-Triggered, Irreversible Conformational Change of SARS-CoV-2 Main Protease on Passing from the Solid State to Aqueous Solution.

The main protease from SARS-CoV-2 is a homodimer. Yet, a recent 0.1-ms-long molecular dynamics simulation performed by D.

The role of water in host-guest interaction.

One of the main applications of atomistic computer simulations is the calculation of ligand binding free energies. The accuracy of these calculations depends on the force field quality and on the thoroughness of configuration sampling. Sampling is an obstacle in simulations due to the frequent appearance of kinetic bottlenecks in the free energy landscape.

Simulation of Liquids with the Tight-Binding Density-Functional Approach and Improved Atomic Charges.

Theoretical description of liquids, especially liquid water, is an ongoing subject with important implications in various domains such as homogeneous catalysis; solvation of molecular, ionic, and biomolecular species; and reactivity. Various formalisms exist to describe liquids, each one displaying its own balance between accuracy and computational cost that defines its range of applications. The present article revisits the ability of the density-functional-based tight-binding (SCC-DFTB) approach to model liquids by focusing on liquid water and liquid benzene under ambient conditions.

Molecular Mechanism of Gas Solubility in Liquid: Constant Chemical Potential Molecular Dynamics Simulations.

Accurate prediction of gas solubility in a liquid is crucial in many areas of chemistry, and a detailed understanding of the molecular mechanism of the gas solvation continues to be an active area of research. Here, we extend the idea of the constant chemical potential molecular dynamics (CμMD) approach to the calculation of the gas solubility in the liquid under constant gas chemical potential conditions. As a representative example, we utilize this method to calculate the isothermal solubility of carbon dioxide in water.

Squeezing Oil into Water under Pressure: Inverting the Hydrophobic Effect.

The molecular structure of dense homogeneous fluid water-methane mixtures has been determined for the first time using high-pressure neutron-scattering techniques at 1.7 and 2.2 GPa.

Insights into the Emerging Networks of Voids in Simulated Supercooled Water.

The structural evolution of supercooled liquid water as we approach the glass transition temperature continues to be an active area of research. Here, we use molecular dynamics simulations of TIP4P/ice water to study the changes in the connected regions of empty space within the liquid, which we investigate using the Voronoi-voids network. We observe two important features: supercooling enhances the fraction of nonspherical voids and different sizes of voids tend to cluster forming a percolating network.

Spontaneously Forming Dendritic Voids in Liquid Water Can Host Small Polymers.

Some liquids are characterized by the presence of large voids with dendritic shapes and for this reason are dubbed transiently porous. By using a battery of data analysis tools, we demonstrate that liquid water and methane are both characterized by transient porosity. We show that the thermodynamics of porosity is distinct from that associated with cavitation á la classical nucleation theory.

Isotope effects of ground and lowest lying vibrational states of H(3-x)D(x)O2(-) complexes.

Isotope effects of the H3O2(-) anion are investigated. For this, the 24 lowest excited vibrational states of the H(3-x)D(x)O2(-) complexes, with x = 0-3, are computed using two different Hamiltonians, namely, a 7D reduced-dimensionality one with a numerical representation of the kinetic energy operator (KEO) and a 9D full-dimensionality Hamiltonian with an exact analytic KEO. The computations are carried out with the multiconfiguration time-dependent Hartree method.

Theoretical study of electronic and tribological properties of h-BNC2/graphene, h-BNC2/h-BN and h-BNC2/h-BNC2 bilayers.

Density functional theory based methods are used to investigate the interlayer sliding energy landscape (ISEL), binding energy and interlayer spacing between h-BNC2/graphene (I), h-BNC2/h-BN (II) and h-BNC2/h-BNC2 (III) bilayer structures for three, six and fourteen different stacking patterns, respectively. Our results show that, in the studied cases, increasing the atomic variety of the ingredient monolayers leads to an ISEL corrugation increase as well. For the studied bilayers the ISEL is obtained by means of the registry index.

Line defects and induced doping effects in graphene, hexagonal boron nitride and hybrid BNC.

Effects on the atomic structure and electronic properties of two-dimensional graphene (G) and h-BN sheets related to the coexistence of dopants and defects are investigated by using density functional theory based methods. Two types of extended line defects are considered for pristine G and h-BN sheets. In these sheets, the presence of individual doping increases the charge transport character.

Theoretical insights into the trends in molecular properties of HCY, HSiY and HGeY molecules where Y = N, P, As.

To obtain insights into the factors that govern the analogy between HCN and its isostructures, HXY where X = C, Si, Ge and Y = N, P, As, the electronic and structural properties of these species in ground, cationic and anionic states at the QCISD, MP2 and B3LYP levels with 6-311++G** basis set and the first exited state with TD-B3LYP method have been presented. The results suggest that there are some correlations between structural and thermodynamic properties of the smallest member of this group (HCN) and heavier congers. The results of computation at these levels also predict the stability of HCAs in the ground state and HCN, HSiN and HGeN in the cationic state from the energetic point of view.