Computationally driven discovery of SARS-CoV-2 M inhibitors: from design to experimental validation.

We report a fast-track computationally driven discovery of new SARS-CoV-2 main protease (M) inhibitors whose potency ranges from mM for the initial non-covalent ligands to sub-μM for the final covalent compound (IC = 830 ± 50 nM). The project extensively relied on high-resolution all-atom molecular dynamics simulations and absolute binding free energy calculations performed using the polarizable AMOEBA force field. The study is complemented by extensive adaptive sampling simulations that are used to rationalize the different ligand binding poses through the explicit reconstruction of the ligand-protein conformation space.

Response to comment on 'Valid molecular dynamics simulations of human hemoglobin require a surprisingly large box size'.

We recently reported that molecular dynamics simulations for hemoglobin require a surprisingly large box size to stabilize the T(0) state relative to R(0), as observed in experiments (El Hage et al., 2018). Gapsys and de Groot have commented on this work but do not provide convincing evidence that the conclusions of El Hage et al.

Valid molecular dynamics simulations of human hemoglobin require a surprisingly large box size.

Recent molecular dynamics (MD) simulations of human hemoglobin (Hb) give results in disagreement with experiment. Although it is known that the unliganded (T[Formula: see text]) and liganded (R[Formula: see text]) tetramers are stable in solution, the published MD simulations of T[Formula: see text] undergo a rapid quaternary transition to an R-like structure. We show that T[Formula: see text] is stable only when the periodic solvent box contains ten times more water molecules than the standard size for such simulations.

A Toolkit to Fit Nonbonded Parameters from and for Condensed Phase Simulations.

The quality of atomistic simulations depends decisively on the accuracy of the underlying energy function (force field). Of particular importance for condensed-phase properties are nonbonded interactions, including the electrostatic and Lennard-Jones terms. Permanent atomic multipoles (MTPs) are an extension to common point-charge (PC) representations in atomistic simulations.

Spatial Averaging: Sampling Enhancement for Exploring Configurational Space of Atomic Clusters and Biomolecules.

Spatial averaging Monte Carlo (SA-MC) is an efficient algorithm dedicated to the study of rare-event problems. At the heart of this method is the realization that from the equilibrium density a related, modified probability density can be constructed through a suitable transformation. This new density is more highly connected than the original density, which increases the probability for transitions between neighboring states, which in turn speeds up the sampling.

Vibrational relaxation and energy migration of N-methylacetamide in water: the role of nonbonded interactions.

Nonequilibrium molecular dynamics (MD) simulations together with physics-based force fields are used to follow energy flow between vibrationally excited N-methylacetamide (NMA) and water. The simulations are carried out with a previously validated force field for NMA, based on a multipolar representation of the electrostatics, and with a new fluctuating point charge model. For the water solvent, a flexible and a rigid model was employed to distinguish between the role of inter- and intramolecular degrees of freedom.