Abstract

ThepKa'softitratablegroupsinproteins,orrathertheshifts relative to the pKa's of single amino acids in solution, are indicators of the local electrostatic environment of the groups. A good understanding of the electrostatic interactions within the solvated protein is required not only for prediction of pKa shifts, but also to gain a better understanding of the pH effects on protein stability and pH dependent conformational changes in proteins. The two primary approaches to modeling protein electrostatic properties are (1) continuum, and (2) explicit solvent models. We have recently completed a study where the solvent dielectric response was evaluated in a system of two oppositely charged ions in solution using explicit solvent; both the Ewald summation and spherical truncation methods were used and compared. From this study, the Ewald sums gave a consistent and expected high dielectric behavior of the solvent. The main goal of this study is to estimate pKa shifts of proteins using large scale simulations of macromolecules in solution that do not suffer from artifacts arising from force truncation. As part of this project, we plan to use explicit solvent simulations of the electrostatic properties of small organics and proteins to parameterize a consistent set of continuum dielectric model parameters.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR006892-09
Application #
6122715
Study Section
Project Start
1999-05-05
Project End
2000-05-04
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
9
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Columbia University (N.Y.)
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027

  Publications

Halgren, Thomas A; Murphy, Robert B; Friesner, Richard A et al. (2004) Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem 47:1750-9
Friesner, Richard A; Banks, Jay L; Murphy, Robert B et al. (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47:1739-49
Baik, Mu-Hyun; Friesner, Richard A; Lippard, Stephen J (2003) Theoretical study of cisplatin binding to purine bases: why does cisplatin prefer guanine over adenine? J Am Chem Soc 125:14082-92
Baik, Mu-Hyun; Friesner, Richard A; Lippard, Stephen J (2002) Theoretical study on the stability of N-glycosyl bonds: why does N7-platination not promote depurination? J Am Chem Soc 124:4495-503
An, Yuling; Friesner, Richard A (2002) A novel fold recognition method using composite predicted secondary structures. Proteins 48:352-66
Gallicchio, Emilio; Zhang, Linda Yu; Levy, Ronald M (2002) The SGB/NP hydration free energy model based on the surface generalized born solvent reaction field and novel nonpolar hydration free energy estimators. J Comput Chem 23:517-29
Standley, D M; Eyrich, V A; An, Y et al. (2001) Protein structure prediction using a combination of sequence-based alignment, constrained energy minimization, and structural alignment. Proteins Suppl 5:133-9
Friesner, R A; Dunietz, B D (2001) Large-scale ab initio quantum chemical calculations on biological systems. Acc Chem Res 34:351-8
Gherman, B F; Dunietz, B D; Whittington, D A et al. (2001) Activation of the C-H bond of methane by intermediate Q of methane monooxygenase: a theoretical study. J Am Chem Soc 123:3836-7
Eyrich, V A; Standley, D M; Friesner, R A (1999) Prediction of protein tertiary structure to low resolution: performance for a large and structurally diverse test set. J Mol Biol 288:725-42

Showing the most recent 10 out of 22 publications