The broad long-term objectives of this work are to develop and apply theoretical models to analyze and to design complementary interactions formed during protein folding and binding. The ability of molecules to recognize one another with appropriate affinity and specificity is central to biology and medicine. The clinical activity of pharmaceutical agents is due largely to their ability to recognize and interfere with one or a small number of molecular targets;undesirable side effects are frequently caused by lack of specificity for the intended target. An important area of research involves understanding the design principles of natural protein molecules and developing tools to engineer modified or entirely new molecules by similar principles. The current proposal focuses on (1) further developments in methodology for the study and engineering of molecular structures and binding partners and (2) applications to particular biological molecules of interest. Methodological enhancements pursued will include improving the robustness of design approaches through a reduction in the rate of false positives, improvement in the balance of packing and electrostatic interactions, and more efficient techniques for treating conformational relaxation. The new methods will be applied to the design and study of novel reagents for structural and cell biology and to computational antibody maturation.

Public Health Relevance

Modern drug therapies are developed through a combination of experimental study and computational design. The research pursued here will improve computational design approaches. The resulting techniques could lead to more rapid development and improved efficacy of new medicines.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function B Study Section (MSFB)
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Preusch, Peter C
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Massachusetts Institute of Technology
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Shen, Yang; Radhakrishnan, Mala L; Tidor, Bruce (2015) Molecular mechanisms and design principles for promiscuous inhibitors to avoid drug resistance: lessons learned from HIV-1 protease inhibition. Proteins 83:351-72
Shen, Yang; Altman, Michael D; Ali, Akbar et al. (2013) Testing the substrate-envelope hypothesis with designed pairs of compounds. ACS Chem Biol 8:2433-41
Nalam, Madhavi N L; Ali, Akbar; Reddy, G S Kiran Kumar et al. (2013) Substrate envelope-designed potent HIV-1 protease inhibitors to avoid drug resistance. Chem Biol 20:1116-24
King, Bracken M; Silver, Nathaniel W; Tidor, Bruce (2012) Efficient calculation of molecular configurational entropies using an information theoretic approximation. J Phys Chem B 116:2891-904
Huggins, David J; Sherman, Woody; Tidor, Bruce (2012) Rational approaches to improving selectivity in drug design. J Med Chem 55:1424-44
Machado, Daniel; Costa, Rafael S; Ferreira, Eugénio C et al. (2012) Exploring the gap between dynamic and constraint-based models of metabolism. Metab Eng 14:112-9
Huggins, David J; Tidor, Bruce (2011) Systematic placement of structural water molecules for improved scoring of protein-ligand interactions. Protein Eng Des Sel 24:777-89
Nalam, Madhavi N L; Ali, Akbar; Altman, Michael D et al. (2010) Evaluating the substrate-envelope hypothesis: structural analysis of novel HIV-1 protease inhibitors designed to be robust against drug resistance. J Virol 84:5368-78
Radhakrishnan, Mala L; Tidor, Bruce (2010) Cellular level models as tools for cytokine design. Biotechnol Prog 26:919-37
Leonard, Effendi; Ajikumar, Parayil Kumaran; Thayer, Kelly et al. (2010) Combining metabolic and protein engineering of a terpenoid biosynthetic pathway for overproduction and selectivity control. Proc Natl Acad Sci U S A 107:13654-9

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