The proposed study will develop and employ computational methods to investigate the relationship between the atomic-level architecture and motion of proteins and their biological function. The emphasis will be on protein-protein association phenomena in aqueous media, dealing with both equilibrium and dynamical aspects of association processes. Attention will be directed toward the crucial solvent and electrolyte effects which mediate macromolecular interactions in physiological aqueous solutions. Area One of study will focus on calculating the thermodynamical free energies characterizing the stability of associated proteins in physiological solution conditions. Specifically, equilibrium constants for gelation of normal human hemoglobin (Hb) versus various sickle cell anemia will be elucidated from the findings of this study. Area Two of study will employ the Brownian dynamics simulation method to calculate both protein-protein and protein-ligand diffusional association rates in order to elucidate the specific structural principles of molecular design which relate to the diffusional encounter stage of biochemical reactions. The methodology thus developed will become one of the tools in the arsenal of computer-aided design of chemical agents with biomedical usefulness. Work will be continued on cytochrome redox partners in the electron transport system. Knowledge of the dynamics of the docking step will permit conclusions regarding the the mechanism of electron transfer between heme proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM034248-03
Application #
3284895
Study Section
Biophysics and Biophysical Chemistry A Study Section (BBCA)
Project Start
1985-09-25
Project End
1991-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Tennessee Technological University
Department
Type
Schools of Arts and Sciences
DUNS #
City
Cookeville
State
TN
Country
United States
Zip Code
38501
Castro, G; Boswell, C A; Northrup, S H (1998) Dynamics of protein-protein docking: cytochrome c and cytochrome c peroxidase revisited. J Biomol Struct Dyn 16:413-24
Mauk, A G; Mauk, M R; Moore, G R et al. (1995) Experimental and theoretical analysis of the interaction between cytochrome c and cytochrome b5. J Bioenerg Biomembr 27:311-30
Northrup, S H; Thomasson, K A; Miller, C M et al. (1993) Effects of charged amino acid mutations on the bimolecular kinetics of reduction of yeast iso-1-ferricytochrome c by bovine ferrocytochrome b5. Biochemistry 32:6613-23
Northrup, S H; Erickson, H P (1992) Kinetics of protein-protein association explained by Brownian dynamics computer simulation. Proc Natl Acad Sci U S A 89:3338-42
Eltis, L D; Herbert, R G; Barker, P D et al. (1991) Reduction of horse heart ferricytochrome c by bovine liver ferrocytochrome b5. Experimental and theoretical analysis. Biochemistry 30:3663-74
Northrup, S H; Wensel, T G; Meares, C F et al. (1990) Electrostatic field around cytochrome c: theory and energy transfer experiment. Proc Natl Acad Sci U S A 87:9503-7
Northrup, S H; Boles, J O; Reynolds, J C (1988) Brownian dynamics of cytochrome c and cytochrome c peroxidase association. Science 241:67-70
Northrup, S H; Luton, J A; Boles, J O et al. (1988) Brownian dynamics simulation of protein association. J Comput Aided Mol Des 1:291-311