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Towards understanding the mechanisms of molecular recognition by computer simulations of ligand–protein interactions
Author(s) -
Verkhivker Gennady M.,
Rejto Paul A.,
Bouzida Djamal,
Arthurs Sandra,
Colson Anthony B.,
Freer Stephan T.,
Gehlhaar Daniel K.,
Larson Veda,
Luty Brock A.,
Marrone Tami,
Rose Peter W.
Publication year - 1999
Publication title -
journal of molecular recognition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.401
H-Index - 79
eISSN - 1099-1352
pISSN - 0952-3499
DOI - 10.1002/(sici)1099-1352(199911/12)12:6<371::aid-jmr479>3.0.co;2-o
Subject(s) - dihydrofolate reductase , cooperativity , chemistry , energy landscape , ligand (biochemistry) , chemical stability , docking (animal) , protein folding , molecular dynamics , folding (dsp implementation) , molecular recognition , affinities , cooperative binding , protein ligand , computational chemistry , binding site , stereochemistry , molecule , receptor , biochemistry , enzyme , medicine , nursing , organic chemistry , electrical engineering , engineering
The thermodynamic and kinetic aspects of molecular recognition for the methotrexate (MTX)–dihydrofolate reductase (DHFR) ligand–protein system are investigated by the binding energy landscape approach. The impact of ‘hot’ and ‘cold’ errors in ligand mutations on the thermodynamic stability of the native MTX–DHFR complex is analyzed, and relationships between the molecular recognition mechanism and the degree of ligand optimization are discussed. The nature and relative stability of intermediates and thermodynamic phases on the ligand–protein association pathway are studied, providing new insights into connections between protein folding and molecular recognition mechanisms, and cooperativity of ligand–protein binding. The results of kinetic docking simulations are rationalized based on the thermodynamic properties determined from equilibrium simulations and the shape of the underlying binding energy landscape. We show how evolutionary ligand selection for a receptor active site can produce well‐optimized ligand–protein systems such as MTX–DHFR complex with the thermodynamically stable native structure and a direct transition mechanism of binding from unbound conformations to the unique native structure. Copyright © 1999 John Wiley & Sons, Ltd.