The overall aim of this project is to improve our understanding of the ab initio structure prediction of single chain polypeptides. Based upon our recent advances in (1) free energy calculations of solvated oligopeptines (Klepeis and Floudas, 1999); (b) deterministic global optimization through the alphaBB approach (Adjiman et al., 1998a,b; Floudas, 2000) and its application to solvated oligopeptides (Klepeis et aL, 1998; Klepeis and Floudas, 1999b); and (c) structure refinement of oligepeptides through sparse NMR restraints (Klepeis et al., 1999), the proposed research is directed at determining the secondary and tertiary structure of polypeptides from the sequence of amino acids without using information available from the databases. We plan to focus on the following objectives: (a) Study a new approach for the identification of the helical segments in monomeric polypeptides that is based on entropic and free energy calculations of overlapping pentapeptides, and treatment of the electrostatics through the nonlinear Poisson-Boltzmann equation. (b) Investigate a novel approach, based upon a mixed-integer optimization framework, for the determination of antiparallel, parallel and multistanded beta sheets, as well as the identification of the disulfide bridges. (c) Study a new approach, based on deterministic global optimization and torsion angle dynamics, for the structure refinement of polypeptides in the presence of sparse restraints that arise either from NmR experiments or through secondary structure information provided by approaches such as those proposed in (a) and (b). (d) Investigate a novel framework for the ab initio structure prediction of single chain polypep tides based on the advances in (a), (b) and (c). (e) Develop distributed computing algorithms for (a), (b), (c) and (d), apply them to polypeptides, and develop tools for the ab initio prediction of three-dimensional structures of polypeptides.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM052032-06
Application #
6604204
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Program Officer
Wehrle, Janna P
Project Start
1996-05-01
Project End
2006-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
6
Fiscal Year
2003
Total Cost
$220,644
Indirect Cost
Name
Princeton University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
Keasar, Chen; McGuffin, Liam J; Wallner, Björn et al. (2018) An analysis and evaluation of the WeFold collaborative for protein structure prediction and its pipelines in CASP11 and CASP12. Sci Rep 8:9939
Khoury, George A; Smadbeck, James; Kieslich, Chris A et al. (2017) Princeton_TIGRESS 2.0: High refinement consistency and net gains through support vector machines and molecular dynamics in double-blind predictions during the CASP11 experiment. Proteins 85:1078-1098
Gorham Jr, Ronald D; Forest, David L; Khoury, George A et al. (2015) New compstatin peptides containing N-terminal extensions and non-natural amino acids exhibit potent complement inhibition and improved solubility characteristics. J Med Chem 58:814-26
Smadbeck, James; Peterson, Meghan B; Zee, Barry M et al. (2014) De novo peptide design and experimental validation of histone methyltransferase inhibitors. PLoS One 9:e95535
Halai, Reena; Bellows-Peterson, Meghan L; Branchett, Will et al. (2014) Derivation of ligands for the complement C3a receptor from the C-terminus of C5a. Eur J Pharmacol 745:176-81
Smadbeck, James; Chan, Kiat Hwa; Khoury, George A et al. (2014) De novo design and experimental characterization of ultrashort self-associating peptides. PLoS Comput Biol 10:e1003718
Khoury, George A; Smadbeck, James; Tamamis, Phanourios et al. (2014) Forcefield_NCAA: ab initio charge parameters to aid in the discovery and design of therapeutic proteins and peptides with unnatural amino acids and their application to complement inhibitors of the compstatin family. ACS Synth Biol 3:855-69
Tamamis, Phanourios; Floudas, Christodoulos A (2014) Elucidating a key component of cancer metastasis: CXCL12 (SDF-1?) binding to CXCR4. J Chem Inf Model 54:1174-88
Khoury, George A; Liwo, Adam; Khatib, Firas et al. (2014) WeFold: a coopetition for protein structure prediction. Proteins 82:1850-68
Tamamis, Phanourios; Floudas, Christodoulos A (2014) Elucidating a key anti-HIV-1 and cancer-associated axis: the structure of CCL5 (Rantes) in complex with CCR5. Sci Rep 4:5447

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