Quantum Mechanics/Molecular Mechanics (QM/MM) Calculations Support a Concerted Reaction Mechanism for the Zika Virus NS2B/NS3 Serine Protease with Its Substrate

Zika virus (ZIKV) is mainly transmitted to humans by Aedes species mosquitoes and is associated with serious pathological disorders including microcephaly in newborns and Guillain–Barré syndrome in adults. Currently, there is no vaccine or anti-ZIKV drug available for preventing or controlling ZIKV infection. An attractive drug target for ZIKV treatment is a two-compartment (NS2B/NS3) serine protease that processes viral polyprotein during infection. Here, conventional molecular dynamics simulations of the ZIKV protease in complex with peptide substrate (TGKRS) sequence at the C-terminus of NS2B show that the substrate is in the active conformation for the cleavage reaction by ZIKV protease. Hybrid quantum mechanics/molecular mechanics (QM/MM) umbrella sampling simulations (PM6/ff14SB) of acylation results reveal that proton transfer from S135 to H51 and nucleophilic attack on the substrate by S135 are concerted. The rate-limiting step involves the formation of a tetrahedral intermediate. In addition, the single-point energy QM/MM calculations, precisely at the level of coupled cluster theory (LCCSD­(T)/(aug)-cc-pVTZ), were performed to correct the potential energy profiles for the first step of the acylation process. The average computed activation barrier at this level of theory is 16.3 kcal mol–1. Therefore, the computational approaches presented here are helpful for further designing of NS2B/NS3 inhibitors based on transition-state analogues

The Body Ontology of Capitalism

Critical social theory powerfully negates symbolic structures of political economy and imaginary projections of ideological culture but never quite knows what to do with corporeal bodies. “The Body Ontology of Capitalism” reviews Marx’s account of body ontology in his post-1859 writings (especially Capital, Vol. 1), in which value (abstract labor) is extracted from the concrete bodies of laborers caught in capital’s grasp. Body ontology is analyzed in Marx’s work as well as Lacan’s psychoanalytic social theory, exploring the relationship between structurally wounded bodies and imaginary projections. Zižek’s embodied account of wounded subjects of sublime ideological objects is also used to interpret the body fantasies of late capitalism (undead, cyborg, armored subjects). Following Marx and psychoanalytic theorists, Krier and Amidon conclude that body ontology is necessary to adequately comprehend and critique symbolic and imaginary productions of capital

Dynamical nonequilibrium molecular dynamics reveals the structural basis for allostery and signal propagation in biomolecular systems

A dynamical approach to nonequilibrium molecular dynamics (D-NEMD), proposed in the 1970s by Ciccotti et al., is undergoing a renaissance and is having increasing impact in the study of biological macromolecules. This D-NEMD approach, combining MD simulations in stationary (in particular, equilibrium) and nonequilibrium conditions, allows for the determination of the time-dependent structural response of a system using the Kubo–Onsager relation. Besides providing a detailed picture of the system’s dynamic structural response to an external perturbation, this approach also has the advantage that the statistical significance of the response can be assessed. The D-NEMD approach has been used recently to identify a general mechanism of inter-domain signal propagation in nicotinic acetylcholine receptors, and allosteric effects in \upbeta -lactamase enzymes, for example. It complements equilibrium MD and is a very promising approach to identifying and analysing allosteric effects. Here, we review the D-NEMD approach and its application to biomolecular systems, including transporters, receptors, and enzymes

Generalized Born Implicit Solvent Models Do Not Reproduce Secondary Structures of De Novo Designed Glu/Lys Peptides

[Image: see text] We test a range of standard generalized Born (GB) models and protein force fields for a set of five experimentally characterized, designed peptides comprising alternating blocks of glutamate and lysine, which have been shown to differ significantly in α-helical content. Sixty-five combinations of force fields and GB models are evaluated in >800 μs of molecular dynamics simulations. GB models generally do not reproduce the experimentally observed α-helical content, and none perform well for all five peptides. These results illustrate that these models are not usefully predictive in this context. These peptides provide a useful test set for simulation methods