Abstract

Our long-range goal is to develop methodologies for drug design based on free energy calculations. We wish to obtain a better understanding of the physical principles that govern the interaction between drugs and proteins. To this end we plan to carry out free energy calculations on HIV-1 protease complexed with various inhibitors for which crystal structures and binding constants are available to us. Particular emphasis will be placed on parameterization of the force field and sampling of the conformations of the protein/inhibitor complex and of the free inhibitor. Macroscopic approaches that have been suggested recently by various groups to estimate free energies of binding will be tested and their utility for data base searches evaluated. Our efforts will include the reverse transcriptase protein of HIV as soon as appropriate high-resolution data on inhibitor complex become available.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
3P01GM039546-10S1
Application #
6107537
Study Section
Project Start
1997-09-01
Project End
1999-08-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
10
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
Yale University
Department
Type
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520

  Publications

Riley, Kasandra J; Steitz, Joan A (2013) The ""Observer Effect"" in genome-wide surveys of protein-RNA interactions. Mol Cell 49:601-4
Brautigam, C A; Aschheim, K; Steitz, T A (1999) Structural elucidation of the binding and inhibitory properties of lanthanide (III) ions at the 3'-5' exonucleolytic active site of the Klenow fragment. Chem Biol 6:901-8
Ota, N; Stroupe, C; Ferreira-da-Silva, J M et al. (1999) Non-Boltzmann thermodynamic integration (NBTI) for macromolecular systems: relative free energy of binding of trypsin to benzamidine and benzylamine. Proteins 37:641-53
Friedman, J M (1999) Interconversion between 3D molecular representations: some macromolecular applications of spherical harmonic-Bessel expansions about an arbitrary center. Comput Chem 23:9-23
Ippolito, J A; Steitz, T A (1998) A 1.3-A resolution crystal structure of the HIV-1 trans-activation response region RNA stem reveals a metal ion-dependent bulge conformation. Proc Natl Acad Sci U S A 95:9819-24
Jaeger, J; Restle, T; Steitz, T A (1998) The structure of HIV-1 reverse transcriptase complexed with an RNA pseudoknot inhibitor. EMBO J 17:4535-42
Brautigam, C A; Steitz, T A (1998) Structural principles for the inhibition of the 3'-5' exonuclease activity of Escherichia coli DNA polymerase I by phosphorothioates. J Mol Biol 277:363-77
Friedman, J M (1997) Fourier-filtered van der Waals contact surfaces: accurate ligand shapes from protein structures. Protein Eng 10:851-63
Mishima, Y; Steitz, J A (1995) Site-specific crosslinking of 4-thiouridine-modified human tRNA(3Lys) to reverse transcriptase from human immunodeficiency virus type I. EMBO J 14:2679-87
Long, K S; Crothers, D M (1995) Interaction of human immunodeficiency virus type 1 Tat-derived peptides with TAR RNA. Biochemistry 34:8885-95

Showing the most recent 10 out of 42 publications