The continual rise of antibiotic resistance presents an urgent need for novel drug development strategies. Computer aided drug design has traditionally focused on targeting rigid enzyme active sites while largely ignoring protein and aqueous structural fluctuations that are critical for enzymatic function. Consequently, the development of antibiotics with high specificity and lasting clinical potency has proven to be exceedingly difficult. To address this challenge, an alluring strategy has been to locate hidden pockets that lie outside of enzyme active sites, called cryptic sites. A coveted target of immense therapeutic interest is TEM-1 Beta-lactamase, an enzyme that harbors a known cryptic site capable of modulating the water mediated cleavage of beta-lactam antibiotics. Unfortunately, the design of a potent antibiotic to occupy the cryptic site has been hindered by limited means of detecting how the site is formed and the mechanism by which it couples to the distant active site and its encompassing hydration structure. Molecular dynamics (MD) simulations of TEM-1 provide direct observation of protein and solvent conformational fluctuations with excellent spatial and temporal resolution. However, MD simulations struggle to access the long-timescale, functionally relevant conformational changes by which cryptic sites are expected to form, even when utilizing state-of-the-art super computers. The Orthogonal Space Tempering (OST) enhanced sampling MD technique was designed to access functional timescales by simultaneously accelerating fluctuations of a targeted dynamic and that of its coupled environment. In this work, a GPU-accelerated version of OST implemented in CHARMM is utilized to observe long-timescale conformational changes of TEM-1 in explicit solvent. To detect the presence of cryptic sites and build an understanding of their couplings, a bespoke toolkit of GPU-accelerated analysis algorithms has been developed. Specifically, these algorithms identify collective motions and map inter-atomic couplings realized by hundreds of thousands of atoms over millions of frames of simulation trajectory; critical tasks for studying cryptic sites made feasible only by GPU programming. The discovery of a water mediated linkage between the cryptic and active sites, along with the detection of a novel cryptic site within TEM-1 are presented.

Discovering and understanding hidden drug binding sites to combat antibiotic resistance: GPU-accelerated study of TEM-1 beta-lactamase

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.