Optimization of electrostatic binding free energy : applications to the analysis and design of ligand binding in protein complexes

Electrostatic interactions play an important role in determining the energetics of association in biomolecular complexes. Previous work has shown that, within a continuum electrostatic model, for any given complex there exists a ligand charge distribution which optimizes the electrostatic binding free energy - the electrostatic complement of the target receptor. This electrostatic affinity optimization procedure was applied to several systems both in order to understand the role of electrostatic interactions in natural systems and as a tool in the design of ligands with improved affinity. Comparison of the natural and optimal charges of several ligands of glutaminyl-tRNA synthetase from E. coli, an enzyme with a strong natural requirement for specificity, shows remarkable similarity in many areas, suggesting that the optimization of electrostatic interactions played a role in the evolution of this system. The optimization procedure was also applied to the design of improvements to two inhibitors of HIV-1 viral-cell membrane fusion. Two tryptophan residues that are part of a D-peptide inhibitor were identified as contributing most significantly to binding, and a novel computational screening procedure based on the optimization methodology was developed to screen a library of tryptophan derivatives at both positions. Additionally, the optimization methodology was used to predict four mutations to standard amino acids at three positions on 5-Helix, a protein inhibitor of membrane fusion. All mutations were computed to improve the affinity of the inhibitor, with a five hundred-fold improvement calculated for one triple mutant.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Chemistry.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2002

Author dc:creator

• Green, David Francis, 1975-

Advisor dc:contributor.advisor

• Bruce Tidor.

• Chemistry.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/16888

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/16888