Computational ligand design and analysis in protein complexes using inverse methods, combinatorial search, and accurate solvation modeling
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2006.
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| Format: | Thesis |
| Language: | eng |
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Massachusetts Institute of Technology
2007
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| Online Access: | http://hdl.handle.net/1721.1/36258 |
| _version_ | 1826210344631009280 |
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| author | Altman, Michael Darren |
| author2 | Bruce Tidor. |
| author_facet | Bruce Tidor. Altman, Michael Darren |
| author_sort | Altman, Michael Darren |
| collection | MIT |
| description | Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2006. |
| first_indexed | 2024-09-23T14:48:20Z |
| format | Thesis |
| id | mit-1721.1/36258 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T14:48:20Z |
| publishDate | 2007 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/362582019-04-10T12:45:33Z Computational ligand design and analysis in protein complexes using inverse methods, combinatorial search, and accurate solvation modeling Altman, Michael Darren 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, 2006. Vita. Includes bibliographical references (p. 207-230). This thesis presents the development and application of several computational techniques to aid in the design and analysis of small molecules and peptides that bind to protein targets. First, an inverse small-molecule design algorithm is presented that can explore the space of ligands compatible with binding to a target protein using fast combinatorial search methods. The inverse design method was applied to design inhibitors of HIV-1 protease that should be less likely to induce resistance mutations because they fit inside a consensus substrate envelope. Fifteen designed inhibitors were chemically synthesized, and four of the tightest binding compounds to the wild-type protease exhibited broad specificity against a panel of drug resistance mutant proteases in experimental tests. Inverse protein design methods and charge optimization were also applied to improve the binding affinity of a substrate peptide for an inactivated mutant of HIV-1 protease, in an effort to learn more about the thermodynamics and mechanisms of peptide binding. A single mutant peptide calculated to have improved binding electrostatics exhibited greater than 10-fold improved affinity experimentally. (cont.) The second half of this thesis presents an accurate method for evaluating the electrostatic component of solvation and binding in molecular systems, based on curved boundary-element method solutions of the linearized Poisson-Boltzmann equation. Using the presented FFTSVD matrix compression algorithm and other techniques, a full linearized Poisson-Boltzmann equation solver is described that is capable of solving multi-region problems in molecular continuum electrostatics to high precision. Michael Darren Altman. Ph.D. 2007-02-21T13:16:27Z 2007-02-21T13:16:27Z 2006 2006 Thesis http://hdl.handle.net/1721.1/36258 77279815 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 230, [2] p. application/pdf Massachusetts Institute of Technology |
| spellingShingle | Chemistry. Altman, Michael Darren Computational ligand design and analysis in protein complexes using inverse methods, combinatorial search, and accurate solvation modeling |
| title | Computational ligand design and analysis in protein complexes using inverse methods, combinatorial search, and accurate solvation modeling |
| title_full | Computational ligand design and analysis in protein complexes using inverse methods, combinatorial search, and accurate solvation modeling |
| title_fullStr | Computational ligand design and analysis in protein complexes using inverse methods, combinatorial search, and accurate solvation modeling |
| title_full_unstemmed | Computational ligand design and analysis in protein complexes using inverse methods, combinatorial search, and accurate solvation modeling |
| title_short | Computational ligand design and analysis in protein complexes using inverse methods, combinatorial search, and accurate solvation modeling |
| title_sort | computational ligand design and analysis in protein complexes using inverse methods combinatorial search and accurate solvation modeling |
| topic | Chemistry. |
| url | http://hdl.handle.net/1721.1/36258 |
| work_keys_str_mv | AT altmanmichaeldarren computationalliganddesignandanalysisinproteincomplexesusinginversemethodscombinatorialsearchandaccuratesolvationmodeling |