Theoretical restrictions on longest implicit time scales in Markov state models of biomolecular dynamics. J Chem Phys. 2018 Jan 28;148(4):044111 Authors: Sinitskiy AV, Pande VS Abstract Markov state models (MSMs)…
Read moreREDOR NMR Reveals Multiple Conformers for a Protein Kinase C Ligand in a Membrane Environment. ACS Cent Sci. 2018 Jan 24;4(1):89-96 Authors: Yang H, Staveness D, Ryckbosch SM, Axtman AD,…
Read more  “In October 2017 we announced the open sourcing of the Folding@Home Android client developed by Sony.  We want to thank everyone who have contributed with CPU time. From the 16th…
Read moreAlthough warfarin is the most widely used anticoagulant worldwide, the mechanism by which warfarin inhibits its target, human vitamin K epoxide reductase (hVKOR), remains unclear. Here we show that warfarin blocks a dynamic electron-transfer process in hVKOR. A major fraction of cellular hVKOR is in an intermediate redox state containing a Cys51-Cys132 disulfide, a characteristic accommodated by a four-transmembrane-helix structure of hVKOR. Warfarin selectively inhibits this major cellular fo…
Read moreThe therapeutic effect of targeted kinase inhibitors can be significantly reduced by intrinsic or acquired resistance mutations that modulate the affinity of the drug for the kinase. In cancer, the majority of missense mutations are rare, making it difficult to predict their impact on inhibitor affinity. This complicates the practice of precision medicine, pairing of patients with clinical trials, and development of next-generation inhibitors. Here, we examine the potential for alchemical free…
Read moreRelated Articles Markov State Models: From an Art to a Science. J Am Chem Soc. 2018 Jan 11;: Authors: Husic BE, Pande VS Abstract Markov state models (MSMs) are a…
Read moreTabtoxinine-β-lactam (TβL), also known as wildfire toxin, is a time- and ATP-dependent inhibitor of glutamine synthetase produced by plant pathogenic strains of Pseudomonas syringae. Here we demonstrate that recombinant glutamine synthetase from Escherichia coli phosphorylates the C3-hydroxyl group of the TβL 3-(S)-hydroxy-β-lactam (3-HβL) warhead. Phosphorylation of TβL generates a stable, noncovalent enzyme-ADP-inhibitor complex that resembles the glutamine synthetase tetrahedral transition …
Read moreProtein stabilization is fundamental to enzyme function and evolution, yet understanding the determinants of a protein’s stability remains a challenge. This is largely due to a shortage of atomically detailed models for the ensemble of relevant protein conformations and their relative populations. For example, the M182T substitution in TEM β-lactamase, an enzyme that confers antibiotic resistance to bacteria, is stabilizing but the precise mechanism remains unclear. Here, we employ Markov stat…
Read moreA minimum variance clustering approach produces robust and interpretable coarse-grained models. J Chem Theory Comput. 2017 Dec 18;: Authors: Husic BE, McKiernan KA, Wayment-Steele HK, Sultan MM, Pande VS Abstract…
Read moreAllosteric drugs, which bind to proteins in regions other than their main ligand-binding or active sites, make it possible to target proteins considered “undruggable” and to develop new therapies that circumvent existing resistance. Despite growing interest in allosteric drug discovery, rational design is limited by a lack of sufficient structural information about alternative binding sites in proteins. Previously, we used Markov State Models (MSMs) to identify such “cryptic pockets,” and here…
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