teamanandtech.org

Proc Natl Acad Sci U S A. 2012 Jul 17;109(29):11681-6. doi: 10.1073/pnas.1209309109. Epub 2012 Jul 2. ABSTRACT Cryptic allosteric sites–transient pockets in a folded protein that are invisible to conventional experiments but can alter enzymatic activity via allosteric communication with the active site–are a promising opportunity for facilitating drug design by greatly expanding the repertoire of available drug targets. Unfortunately, identifying these sites is difficult, typically requiring resource-intensive screening of large libraries of small molecules. Here, we demonstrate that Markov state models built from extensive computer simulations (totaling hundreds of microseconds of dynamics) can identify prospective cryptic sites from the equilibrium fluctuations of three medically relevant proteins–β-lactamase,...

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