This proposal describes new methods for protein secondary structure prediction, tertiary folding to low resolution using reduced protein models, and structural refinement using atomic level potential functions and a continuum model for the solvation free energy. The methods will be applied to ab initio prediction of protein structure, threading, loop refinement in homology modeling, and protein structure determination from sparse NMR datasets. Specific methodological areas of focus include: (1) new scoring functions for secondary structure prediction; (2) development of a reduced potential function, and global optimization methods for tertiary folding; (3) construction of a polarizable protein potential function using ab initio quantum chemical data; (4) improvement of Poisson-Boltzmann and generalized Born continuum solvation models; (5) inclusion of NMR constraints in the tertiary folding methodology.
| Wang, Lingle; Berne, B J; Friesner, Richard A (2012) On achieving high accuracy and reliability in the calculation of relative protein-ligand binding affinities. Proc Natl Acad Sci U S A 109:1937-42 |
| Zhao, Suwen; Zhu, Kai; Li, Jianing et al. (2011) Progress in super long loop prediction. Proteins 79:2920-35 |
| Abel, Robert; Wang, Lingle; Friesner, Richard A et al. (2010) A displaced-solvent functional analysis of model hydrophobic enclosures. J Chem Theory Comput 6:2924-2934 |
| Trbovic, Nikola; Cho, Jae-Hyun; Abel, Robert et al. (2009) Protein side-chain dynamics and residual conformational entropy. J Am Chem Soc 131:615-22 |
| Abel, Robert; Young, Tom; Farid, Ramy et al. (2008) Role of the active-site solvent in the thermodynamics of factor Xa ligand binding. J Am Chem Soc 130:2817-31 |
| Trbovic, Nikola; Kim, Byungchan; Friesner, Richard A et al. (2008) Structural analysis of protein dynamics by MD simulations and NMR spin-relaxation. Proteins 71:684-94 |
| Felts, Anthony K; Gallicchio, Emilio; Chekmarev, Dmitriy et al. (2008) Prediction of Protein Loop Conformations using the AGBNP Implicit Solvent Model and Torsion Angle Sampling. J Chem Theory Comput 4:855-868 |
| Hagen, Morten; Kim, Byungchan; Liu, Pu et al. (2007) Serial replica exchange. J Phys Chem B 111:1416-23 |
| Xiang, Zhexin; Steinbach, Peter J; Jacobson, Matthew P et al. (2007) Prediction of side-chain conformations on protein surfaces. Proteins 66:814-23 |
| Huang, Xuhui; Hagen, Morten; Kim, Byungchan et al. (2007) Replica exchange with solute tempering: efficiency in large scale systems. J Phys Chem B 111:5405-10 |
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