Electrostatics and packing in biomolecules : accounting for conformational change in protein folding and binding

The role of electrostatics and packing in protein folding and molecular association was assessed in different biomolecular systems. A continuum electrostatic model was applied to long-range electrostatic effects in the binding of human carbonic anhydrase II to a sulfonamide inhibitor. The effect of chemically modifying lysine e-amino groups was computed, and the average calculated value showed good agreement with experimental results determined by capillary electrophoresis. In a second study, the continuum model was used to analyze all the electrostatic interactions in the Zif268 protein-DNA complex. The net electrostatic effect was unfavorable to binding, although many individual groups or group pairs had a favorable effect, and the residues most unfavorable to binding correspond to those thought to be important for specificity. Also, a measure of electrostatic complementarity was developed and applied to myoglobin-both to known sequences and to hypothetical chimeric myoglobin sequences. The complementarity measure rated the correct myoglobins higher than chimeric myoglobins when crystal structures were used, and performed better than other readily available measures of complementarity when myoglobin homology models were evaluated. In the second part of the thesis, methods for repacking proteins were presented and applied to Arc repressor. Sequence variants that are predicted to fold as heterodimers preferentially and variants that favor a switch-Arc structure over wild-type were found.

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

• Caravella, Justin Andrew, 1974-

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/1721.1/16823

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/16823