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Publication Abstract from PubMed

Undecaprenyl pyrophosphate synthase (UPPS) is a cis-prenyltransferase enzyme, which is required for cell-wall biosynthesis in bacteria. UPPS is an attractive target for anti-microbial therapy. We performed long molecular dynamics (MD) simulations and docking studies on UPPS to investigate its dynamic behavior and the influence of protein flexibility on the design of UPPS inhibitors. We also describe the first x-ray crystallographic structure of E. coli apo-UPPS. The MD simulations indicate that UPPS is a highly flexible protein, with mobile binding pockets in the active site. By carrying out docking studies with experimentally validated UPPS inhibitors using high and low populated conformational states extracted from the MD simulations, we show that structurally dissimilar compounds can bind preferentially to different and rarely sampled conformational states. By performing structural analyses on the newly obtained apo-UPPS and other crystal structures previously published, we show that the changes observed during the MD simulation are very similar to those seen in the crystal structures obtained in the presence or absense of ligands. We believe that this is the first time that a rare "expanded pocket" state, a key to drug design and verified by crystallography, has been extracted from an MD simulation.

Applying Molecular Dynamics Simulations to Identify Rarely Sampled Ligand-bound Conformational States of Undecaprenyl Pyrophosphate Synthase, an Antibacterial Target.,Sinko W, de Oliveira C, Williams S, Van Wynsberghe A, Durrant JD, Cao R, Oldfield E, Andrew McCammon J Chem Biol Drug Des. 2011 Feb 5. doi: 10.1111/j.1747-0285.2011.01101.x. PMID:21294851^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.