Mass-weighted molecular dynamics simulation of the protein-ligand complex of rhizopuspepsin and inhibitor

• Published in: Biophysical journal Vol. 60; no. 4; pp. 966 - 973
• Main Author: Mao, B.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.10.1991; Biophysical Society
• Subjects: Amino Acid Sequence; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - metabolism; aspartic proteinases; binding sites; Biological and medical sciences; computer simulation; Conformational dynamics in molecular biology; crystals; Fundamental and applied biological sciences. Psychology; Ligands; Models, Molecular; Molecular biophysics; molecular conformation; Molecular Sequence Data; Molecular Weight; Oligopeptides - metabolism; Protease Inhibitors - metabolism; Protein Binding; Protein Conformation; proteinase inhibitors; Rhizopus; rhizopus chinensis; simulation models; Ligand binding; Enzyme; Conformational dynamics; Enzyme inhibitor; Inhibitor enzyme complex; Pepsin; Binding site; Spatial structure; Conformation
• ISSN: 0006-3495; 1542-0086
• DOI: 10.1016/S0006-3495(91)82130-0

The mass-weighted molecular dynamics simulation method was developed previously for sampling the multidimensional conformational space of linear and cyclic polypeptides and studying their conformational flexibility. Herein results from molecular dynamics simulations of the protein-ligand complex of the aspartyl protease rhizopuspepsin and a polypeptide inhibitor are reported. The dihedral conformational space sampling for the linear peptide inhibitor in situ was found to be increased in the mass-weighted simulation as in other molecular systems previously studied. More significantly, the physical space of the enzyme binding pocket was also sampled efficiently in the simulations and multiple binding sites were identified for the inhibitor. These results suggest that it may be possible now to study, by computer simulations, the putative initial enzyme-inhibitor complex suggested experimentally from the time-dependent kinetics of enzyme inhibition by slow-binding inhibitors (Morrison, J. F., and C. T. Walsh. 1988. Adv. Enzymol. 61:201), and/or conformational substates in protein-ligand complexes suggested in the study of reassociation dynamics of myoglobin and carbon monoxide following photolysis (Austin, R. H., K. W. Beeson, L. Eisenstein, H. Frauenfelder, and I. C. Gunsalus. 1975. Biochemistry. 14:5355). Moreover, the intermediate binding steps and the molecular flexibility of the inhibitor shown in the MWMD simulation may have crucial roles in the ligand binding process.