Energy calculations and analysis of HIV-1 protease-inhibitor crystal structures

Abstract

The interactions between HIV-1 protease and its bound inhibitors have been investigated by molecular mechanics calculations and by analysis of crystal structures of the complexes in order to determine general rules for inhibitor and substrate binding to the protease. Fifteen crystal structures of HIV-1 protease with different peptidomimetic inhibitors showed conservation of hydrogen bond interactions between the main chain C = O and NH groups of the inhibitors and the C = O and NH groups of the protease extending from P3 C = O to P3' NH. The mean length of the hydrogen bonds between the inhibitor and the flexible flaps and the conserved water molecule (2.9 A) is slightly shorter than the mean length of hydrogen bonds between the inhibitor and the more rigid active site region (3.1 A) of the protease. The two hydrogen bonds between the conserved water and P2 and P1' carbonyl oxygen atoms of the inhibitor are the shortest and are predicted to be important for the tight binding of inhibitors. Molecular mechanics analysis of three crystal structures of HIV-1 protease with different inhibitors with independent calculations using the programs Discover and Brugel gave an estimate of 56-68% for the contribution of all the inhibitor main chain atoms to the total calculated protease-inhibitor interaction energy. The contribution of individual inhibitor residues to the interaction energy was calculated using Brugel. The main chain atoms of residue P2 had a consistently large favorable contribution to the total interaction energy, probably due to the presence of the two short hydrogen bonds to the flexible flap.(ABSTRACT TRUNCATED AT 250 WORDS)

Anatomy of protein pockets and cavities: Measurement of binding site geometry and implications for ligand design

“…HIV-I protease has perhaps the largest number of independently determined protein-inhibitor crystal structures (Vondrasek & Wlodawer, 1997), and design and analysis of its inhibitors is an area of vigorous study (Navia et al, 1989;Wlodawer et al, 1989;Wlodawer & Erickson, 1993;Gustchina et al, 1994;Vondrasek et al, 1997). The active site is symmetrically formed by both subunits of the homodimer (green, Fig.…”

A preference-based free-energy parameterization of enzyme-inhibitor binding. Applications to HIV-1-protease inhibitor design

“…These interactions result in an almost complete burial of most HIV-I-PR inhibitors. Conclusions about the energetic contributions to the total binding strength of these inhibitors, based largely on applications of conventional modeling tools (Hutchins & Greer, 1991;Appelt, 1993;Guida, 1994;Chen & Tropsha, 1995;Holloway et al, 1995), find that hydrogen bonding patterns and hydrophobic interactions are frequent components of inhibitor binding (Appelt, 1993;Wlodawer & Erickson, 1993;Gustchina et al, 1994). The extent and importance of these interactions have, however, been difficult to characterize.…”

Crystal structure of human T cell leukemia virus protease, a novel target for anticancer drug design

“…The inhibitor is bound in an extended conformation (Fig. 4), which is typical for peptidic and peptidomimetic ligands bound to retroviral PRs, and each carbonyl oxygen and amide group of its backbone participates in direct hydrogen bonds with the enzyme in an identical manner to those previously reported for the other retroviral PRs (30). Four hydrogen bonds between the enzyme and inhibitor, mediated by a water molecule, represent the canonical interactions between the flaps and backbone carbonyls of the P2 and P1Ј inhibitor residues.…”