1,081 research outputs found
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 GuillaināBarreĢ
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 (LCCSDĀ(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 molā1. Therefore, the
computational approaches presented here are helpful for further designing
of NS2B/NS3 inhibitors based on transition-state analogues
Beneficial substrate partitioning boosts non-aqueous catalysis in de novo enzyme-alginate beads
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. āThe Body Ontology of Capitalismā reviews Marxās 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 capitalās grasp. Body ontology is analyzed in Marxās work as well as Lacanās psychoanalytic social theory, exploring the relationship between structurally wounded bodies and imaginary projections. Zižekās 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
Crystallography and QM/MM Simulations Identify Preferential Binding of Hydrolyzed Carbapenem and Penem Antibiotics to the L1 Metallo-Ī²-Lactamase in the Imine Form
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 KuboāOnsager relation. Besides providing a detailed picture of the systemās 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
Multiscale Methods in Drug Design Bridge Chemical and Biological Complexity in the Search for Cures
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 Ī±-helical content. Sixty-five combinations of force fields and GB models are evaluated in >800 Ī¼s of molecular dynamics simulations. GB models generally do not reproduce the experimentally observed Ī±-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
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