Elucidating Atomistic Insight into the Dynamical Responses of the SARS-CoV-2 Main Protease for the Binding of Remdesivir Analogues: Leveraging Molecular Mechanics To Decode the Inhibition Mechanism.

To combat mischievous coronavirus disease followed by continuous upgrading of therapeutic strategy against the antibody-resistant variants, the molecular mechanistic understanding of protein-drug interactions is a prerequisite in the context of target-specific rational drug development. Herein, we attempt to decipher the structural basis for the inhibition of SARS-CoV-2 main protease (Mpro) through the elemental analysis of potential energy landscape and the associated thermodynamic and kinetic properties of the enzyme-inhibitor complexes using automated molecular docking calculations in conjunction with classical force field-based molecular dynamics (MD) simulations. The crux of the scalable all-atom MD simulations consummated in explicit solvent media is to capture the structural plasticity of the viral enzyme due to the binding of remdesivir analogues and ascertain the subtle interplay of noncovalent interactions in stabilizing specific conformational states of the receptor that controls the biomolecular processes related to the ligand binding and dissociation kinetics. To unravel the critical role of modulation of the ligand scaffold, we place further emphasis on the estimation of binding free energy as well as the energy decomposition analysis by employing the generalized Born and Poisson-Boltzmann models. The estimated binding affinities are found to vary between -25.5 and -61.2 kcal/mol. Furthermore, the augmentation of inhibitory efficacy of the remdesivir analogue crucially stems from the van der Waals interactions with the active site residues of the protease. The polar solvation energy contributes unfavorably to the binding free energy and annihilates the contribution of electrostatic interactions as derived from the molecular mechanical energies.

4d and 5d bimetal doped tubular silicon clusters Si12M2 with M = Nb, Ta, Mo and W: a bimetallic configuration model.

Geometries and electronic properties related to the ground state stabilities of several Si12M2 clusters (M: second-row (Nb and Mo) and third-row (Ta and W) transition metals, and their mixed bimetallic clusters M2: NbMo and TaW) were explored using density functional theory (DFT) computations. The computed results show that two different structural motifs emerge as the global energy minima of such clusters. They are basically singlet tubular structures in either a C2v prism (1A1) or a C6v antiprism (1A1) form. Other structural shapes are also possible for higher-energy isomers and in higher spin states. 58-valence electron systems including Nb2Si12, Ta2Si12, Mo2Si122+, W2Si122+, NbMoSi12+ and TaWSi12+ are thermodynamically stable as C2v prism global minima on the corresponding potential energy surfaces. Clusters containing 60 valence electrons include Mo2Si12, W2Si12, Nb2Si122-, Ta2Si122-, NbMoSi12- and TaWSi12- and they prefer a C6v anti-prism form. In the mixed MoNbSi12 and TaWSi12 open-shell systems, both resulting C2 (2A) and C2v (2A1) forms are nearly degenerate. The formation of Si12M2 clusters in such specific ground state symmetry is explained using the Jellium model and orbital interaction analyses. The investigations lead further to a proposal for a simple model of a bimetallic configuration using the nature of interactions of the transition metal d-d dimeric bond with the Si12 host, to interpret the formation of such M2Si12 clusters.

Electronic structures and thermochemical properties of the small silicon-doped boron clusters B(n)Si (n=1-7) and their anions.

We perform a systematic investigation on small silicon-doped boron clusters B(n)Si (n=1-7) in both neutral and anionic states using density functional (DFT) and coupled-cluster (CCSD(T)) theories. The global minima of these B(n)Si(0/-) clusters are characterized together with their growth mechanisms. The planar structures are dominant for small B(n)Si clusters with n≤5. The B(6)Si molecule represents a geometrical transition with a quasi-planar geometry, and the first 3D global minimum is found for the B(7)Si cluster. The small neutral B(n)Si clusters can be formed by substituting the single boron atom of B(n+1) by silicon. The Si atom prefers the external position of the skeleton and tends to form bonds with its two neighboring B atoms. The larger B(7)Si cluster is constructed by doping Si-atoms on the symmetry axis of the B(n) host, which leads to the bonding of the silicon to the ring boron atoms through a number of hyper-coordination. Calculations of the thermochemical properties of B(n)Si(0/-) clusters, such as binding energies (BE), heats of formation at 0 K (ΔH(f)(0)) and 298 K (ΔH(f)([298])), adiabatic (ADE) and vertical (VDE) detachment energies, and dissociation energies (D(e)), are performed using the high accuracy G4 and complete basis-set extrapolation (CCSD(T)/CBS) approaches. The differences of heats of formation (at 0 K) between the G4 and CBS approaches for the B(n)Si clusters vary in the range of 0.0-4.6 kcal mol(-1). The largest difference between two approaches for ADE values is 0.15 eV. Our theoretical predictions also indicate that the species B(2)Si, B(4)Si, B(3)Si(-) and B(7)Si(-) are systems with enhanced stability, exhibiting each a double (σ and π) aromaticity. B(5)Si(-) and B(6)Si are doubly antiaromatic (σ and π) with lower stability.

Thermodynamic properties of germanium/carbon microclusters.

Theoretical studies on the Ge(n)C(m) (n=1,2; m=1-3) microclusters have been performed using the state of the art calculations. Several alternative structures of these clusters were studied to locate the lowest-energy isomers. It is observed that the structures of the complexes result from the competition between ionic Ge-C, conjugated covalent C-C, and metallic Ge-Ge bonds. The ionization of the molecules enhances the ionic character of the Ge-C bond and has significant structural consequences. Using theoretically determined partition functions, thermodynamic data are computed and experimental enthalpies are enhanced. The ab initio atomization energies of germanium carbides compare well with corrected experimental functions. The experimental appearance potentials are well reproduced by the theoretical ionization potentials.