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Energy functions for protein structure prediction
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Andrei L.Lomize
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Efficient methods for protein structure prediction, de novo design and ligand docking require energy optimization. An especially important goal here is the correct evaluation of free energy differences, not enthalpy in vacuum that is usually calculated with molecular mechanics potentials. The required energy functions must take into account conformational entropy, solvation free energy, and the dependence of interatomic interactions on the environment. They must be also tested against the experimental thermodynamic stabilities of proteins or protein-ligand complexes.
Recently, we have determined van der Waals (vdW) interaction energies between different atom types, energies of hydrogen bonds, and atomic solvation parameters from the published free-energy differences for 106 mutants with replacements of buried uncharged residues and available crystal structures [Lomize et al., 2002]. The obtained energies of interatomic interactions were different from that in molecular mechanics in three important aspects:
(1) they describe interactions in the protein interior rather than in vacuum;
(2) they are generally weaker and follow like-dissolves-like rule;
(3) they are related to enthalpy of melting, rather than to enthalpy of sublimation.
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Thermodynamic cycle applied for calculation of ΔΔG.
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The developed energy functions are especially useful for the design of a full-atomic threading procedure, which would allow a comparative modeling of proteins that are remotely related to their experimental templates.
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In the future, we will address two major problems in this field: (1) quantification of interactions at the water-protein interface and contributions of charged groups, and (2) operating with ΔG rather than ΔΔG values. The parameterization of different free energy contributions will be accomplished based on a variety of published experimental data, such as unfolding free energies, ligand binding constants, ΔpKa of charged groups in proteins, and fusion enthalpies of organic compounds.
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Related Publications
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Lomize AL, Reibarkh MY, Pogozheva ID
Interatomic potentials and solvation parameters from protein engineering data for buried residues.
Protein Sci., 11: 1984-2000 (2002)
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Lomize AL, Mosberg HI
Thermodynamic model of secondary structure for alpha-helical peptides and proteins.
Biopolymers., 42: 239-269 (1997)
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Lomize AL, Pogozheva ID, Mosberg HI
Prediction of protein structure: The problem of fold multiplicity.
Proteins, 37: 199-203 (1999)
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Lomize AL, Pogozheva ID, Mosberg HI
Quantification of helix-helix binding affinities in micelles and lipid bilayers.
Protein Sci., 13: 2600-2612 (2004)
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External Funding
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R21 GM61299, A. L. Lomize, PI
NIH/NIGM
Thermodynamic model of transmembrane alpha-bundles
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