Sage Journals: Discover world-class research

Abstract

As an outgrowth of our small molecule modeling effort, we have begun to develop a large molecule modeling system. This new effort centers around a VAX 11/780 coupled to an Evans and Sutherland Color Multi-Picture system. The software currently available is A. Jones' FRODO program for display and manipulation, M. Connolly's SURFACE program, A. Hagler's VFF energy calculation program, and a variety of small programs written in-house. The structure and capabilities of this system will be described. An application of the system to studying the mechanism of peptide cleavage by the zinc endopeptidase thermolysin will be presented. This investigation has led us to suggest a number of modifications to the previously proposed mechanism and offers a rationalization for published substrate data.

Keywords

Merck Molecular Modeling System (MMMS)Computational chemistry Computer graphics Mechanism Thermolysin Zinc peptidase

Get full access to this article

View all access options for this article.

References

Homes

Matthews

: Structure of thermolysin refined at 1.6 Å resolution. J Mol Biol 1982; 160: 623–639.

Weaver

Kester

Matthews

: A crystallographic study of the complex of phosphoramidon with thermolysin. A model for the presumed catalytic transition state and for the binding of extended substrates. J Mol Biol 1977; 114: 119–132.

Maycock

DeSousa

Payne

ten Broeke

Patchett

: Inhibition of thermolysin by N-carboxymethyl dipeptides. Biochem Biophys Res Commun 1981; 102: 963–969.

Kester

Matthews

: Crystallographic study of the binding of dipeptide inhibitors to thermolysin: Implications for the mechanism of catalysis. Biochemistry 1977; 16: 2506–2516.

Holmes

Matthews

: Binding of hydroxamic acid inhibitors to crystalline thermolysin suggests a pentacoordinate zinc intermediate in catalysis. Biochemistry 1981; 20: 6912–6920.

Morgan

Fruton

: Kinetics of the action of thermolysin on peptide substrates. Biochemistry 1978; 17: 3562–3568.

Intermolecular Modeling Methods in Drug Design/Modeling the Mechanism of Peptide Cleavage by Thermolysin

Abstract

Keywords

Get full access to this article

References