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Protein Science (2004), 13:513-528. Published by Cold Spring Harbor Laboratory Press. Copyright © 2004 The Protein Society
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The role of hydrogen bonding in the enzymatic reaction catalyzed by HIV-1 protease

Joanna Trylska1,2, Pawel Grochowski2 and J. Andrew McCammon1,3

1 Department of Chemistry and Biochemistry and Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, California 92093, USA
2 Interdisciplinary Centre for Mathematical and Computational Modelling, Warsaw University, Pawinskiego 5a, 02-106 Warsaw, Poland
3 Howard Hughes Medical Institute and Department of Pharmacology, University of California at San Diego, La Jolla, California 92093, USA

(RECEIVED August 13, 2003; FINAL REVISION October 9, 2003; ACCEPTED October 10, 2003)



Abstract

The hydrogen-bond network in various stages of the enzymatic reaction catalyzed by HIV-1 protease was studied through quantum-classical molecular dynamics simulations. The approximate valence bond method was applied to the active site atoms participating directly in the rearrangement of chemical bonds. The rest of the protein with explicit solvent was treated with a classical molecular mechanics model. Two possible mechanisms were studied, general-acid/general-base (GA/GB) with Asp 25 protonated at the inner oxygen, and a direct nucleophilic attack by Asp 25. Strong hydrogen bonds leading to spontaneous proton transfers were observed in both reaction paths. A single-well hydrogen bond was formed between the peptide nitrogen and outer oxygen of Asp 125. The proton was diffusely distributed with an average central position and transferred back and forth on a picosecond scale. In both mechanisms, this interaction helped change the peptide-bond hybridization, increased the partial charge on peptidyl carbon, and in the GA/GB mechanism, helped deprotonate the water molecule. The inner oxygens of the aspartic dyad formed a low-barrier, but asymmetric hydrogen bond; the proton was not positioned midway and made a slightly elongated covalent bond, transferring from one to the other aspartate. In the GA/GB mechanism both aspartates may help deprotonate the water molecule. We observed the breakage of the peptide bond and found that the protonation of the peptidyl amine group was essential for the peptide-bond cleavage. In studies of the direct nucleophilic mechanism, the peptide carbon of the substrate and oxygen of Asp 25 approached as close as 2.3 Å.

Keywords: enzymatic reaction; valence bond method; hydrogen bond; proton transfer; molecular dynamics simulations

Reprint requests to: Joanna Trylska, Department of Chemistry and Biochemistry, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; e-mail: jtrylska{at}mccammon.ucsd.edu; fax: (858) 534-7042.

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.03372304.


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