Electrostatics and packing in biomolecules : accounting for conformational change in protein folding and binding
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2002.
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| Format: | Thesis |
| Language: | eng |
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Massachusetts Institute of Technology
2005
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| Online Access: | http://hdl.handle.net/1721.1/16823 |
| _version_ | 1826197204063223808 |
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| author | Caravella, Justin Andrew, 1974- |
| author2 | Bruce Tidor. |
| author_facet | Bruce Tidor. Caravella, Justin Andrew, 1974- |
| author_sort | Caravella, Justin Andrew, 1974- |
| collection | MIT |
| description | Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2002. |
| first_indexed | 2024-09-23T10:44:06Z |
| format | Thesis |
| id | mit-1721.1/16823 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T10:44:06Z |
| publishDate | 2005 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/168232019-04-10T12:44:52Z Electrostatics and packing in biomolecules : accounting for conformational change in protein folding and binding Caravella, Justin Andrew, 1974- Bruce Tidor. Massachusetts Institute of Technology. Dept. of Chemistry. Massachusetts Institute of Technology. Dept. of Chemistry. Chemistry. Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2002. Includes bibliographical references (p. 189-205). This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. 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. (cont.) In a final set of calculations, the search algorithms for repacking were combined with electrostatic effects predicted from an approximate continuum model. The structure of Zif268 zinc finger 1 complexed to DNA was predicted when limited docking and side chain flexibility were allowed. The predicted structure shows good agreement with the x-ray crystal structure. A second repacked structure provides insight into how sequence changes affect structure and hence binding specificity in the zinc finger protein. by Justin Andrew Caravella. Ph.D. 2005-05-19T14:44:25Z 2005-05-19T14:44:25Z 2002 2002 Thesis http://hdl.handle.net/1721.1/16823 51026227 eng 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. http://dspace.mit.edu/handle/1721.1/7582 205 p. 3943472 bytes 3943185 bytes application/pdf application/pdf application/pdf Massachusetts Institute of Technology |
| spellingShingle | Chemistry. Caravella, Justin Andrew, 1974- Electrostatics and packing in biomolecules : accounting for conformational change in protein folding and binding |
| title | Electrostatics and packing in biomolecules : accounting for conformational change in protein folding and binding |
| title_full | Electrostatics and packing in biomolecules : accounting for conformational change in protein folding and binding |
| title_fullStr | Electrostatics and packing in biomolecules : accounting for conformational change in protein folding and binding |
| title_full_unstemmed | Electrostatics and packing in biomolecules : accounting for conformational change in protein folding and binding |
| title_short | Electrostatics and packing in biomolecules : accounting for conformational change in protein folding and binding |
| title_sort | electrostatics and packing in biomolecules accounting for conformational change in protein folding and binding |
| topic | Chemistry. |
| url | http://hdl.handle.net/1721.1/16823 |
| work_keys_str_mv | AT caravellajustinandrew1974 electrostaticsandpackinginbiomoleculesaccountingforconformationalchangeinproteinfoldingandbinding |