Analysis of the structure of chemically synthesized HIV-1 protease complexed with a hexapeptide inhibitor. Part I: Crystallographic refinement of 2 Å data

Abstract

The structure of a complex between a hexapeptide-based inhibitor, MVT-101, and the chemically synthesized (Aba 67,95,167,195; Aba: L-a-amino-n-butyric acid) protease from the human immunodeficiency virus (HIV-1), reported previously at 2.3 Å has now been refined to a crystallographic R factor of 15.4% at 2.0 Å resolution. Root mean square deviations from ideality are 0.18 Å for bond lengths and 2.4° for the angles. The inhibitor can be fitted to the difference electron density map in two alternative orientations. Drastic differences are observed for positions and interactions at P3/S3 and P38/S38 subsites of the two orientations due to different crystallographic environments. Proteins 27:184-194 r 1997 Wiley-Liss, Inc. †

How inaccuracies in protein structure models affect estimates of protein–ligand interactions: Computational analysis of HIV‐I protease inhibitor binding

“…Partial atomic charges and the all‐hydrogens parameters for van der Waals and bonded energy terms for the 16 ligands have been previously determined 7. Depending on the inhibitor, either residue Asp25 or Asp25′ of the HIV‐I protease can be protonated in a complex 16, 26–28. In our work, to facilitate comparisons, protonation of Asp25 for all protein–ligand complexes is assumed.…”

Thermodynamic linkage between the binding of protons and inhibitors to HIV‐1 protease

“…Accordingly, the present study uses the PB method to compute the protonation states of the aspartyl dyad of free HIV-1 PR and of HIV-1 PR complexed with four inhibitors that interact intimately with the aspartyl dyad. One inhibitor, MVT-101~Miller et al, 1989!~Fig. 1A!, contains a basic secondary amine that lies within 3-4 Å of the carboxyl oxygens of the aspartyl dyad~Miller et Miller et al, 1997!. This inhibitor has been studied previously by MD simulations, as noted above~Harte Geller et al, 1997!.…”

“…Harte & Beveridge, 1993!. Crystal structures are available for both complexes~Miller et al, 1989;Jaskolski et al, 1991;Miller et al, 1997!. For both complexes, a separate simulation was carried out for each of the four possible protonation states of the aspartyl dyad,~0, 0!,~Ϫ1, 0!,~0, Ϫ1!, and~Ϫ1, Ϫ1!, and for each complex, a single protonation state led to a trajectory that preserved the crystallographically determined conformation of the active site particularly well.…”

EURADIA, the European Research Area in Diabetes

“…Our selection of structural variables was made regarding several previously reported X‐ray crystallographic structure of HIV‐1 protease inhibitor complexes that revealed a binding mode in which the central hydroxyl group and the amino groups interact with the catalytic Asp25 and Asp25′ residues of the enzyme, while the carbonyl groups of the inhibitors accepted additional hydrogen bonds 20–27. This set of chemical variables gave good results in a previous work of ours, a chemometric multivariate analysis of hidroxyethylene‐like HIV‐1 protease inhibitors 9.…”