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  • 1
    Electronic Resource
    Electronic Resource
    The magnitude of the backbone conformational entropy change in protein folding (1996)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 25 (1996), S. 143-156 
    Details
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The magnitude of the conformational entropy change experienced by the peptide backbone upon protein folding was investigated experimentally and by computational analysis. Experimentally, two different pairs of mutants of a 33 amino acid peptide corresponding to the leucine zipper region of GCN4 were used for high-sensitivity microcalorimetric analysis. Each pair of mutants differed only by having alanine or glycine at a specific solvent-exposed position under conditions in which the differences in stability could be attributed to differences in the conformational entropy of the unfolded state. The mutants studied were characterized by different stabilities but had identical heat capacity changes of unfolding (ΔCp), identical solvent-related entropies of unfolding (ΔSsolv), and identical enthalpies of unfolding (ΔH) at equivalent temperatures. Accordingly, the differences in stability between the different mutants could be attributed to differences in conformational entropy. The computational studies were aimed at generating the energy profile of backbone conformations as a function of the main chain dihedral angles φ and ϱ. The energy profiles permit a direct calculation of the probability distribution of different conformers and therefore of the conformational entropy of the backbone. The experimental results presented in this paper indicate that the presence of the methyl group in alanine reduces the conformational entropy of the peptide backbone by 2.46 ± 0.2 cal/K · mol with respect to that of glycine, consistent with a 3.4-fold reduction in the number of allowed conformations in the alanine-containing peptides. Similar results were obtained from the energy profiles. The computational analysis also indicates that the addition of further carbon atoms to the side chain had only a small effect as long as the side chains were unbranched at position β. A further reduction with respect to Ala of only 0.61 and 0.81 cal/K · mol in the backbone entropy was obtained for leucine and lysine, respectively. β-branching (Val) produces the largest decrease in conformational entropy (1.92 cal/K · mol less than Ala). Finally, the backbone entropy change associated with the unfolding of an α-helix is 6.51 cal/K · mol for glycine. These and previous results have allowed a complete estimation of the conformational entropy changes associated with protein folding. © 1996 Wiley-Liss, Inc.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.1
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    The enthalpy change in protein folding and binding: Refinement of parameters for structure-based calculations (1996)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 26 (1996), S. 123-133 
    Details
    ISSN: 0887-3585
    Keywords: enthalpy ; thermodynamics ; folding/unfolding ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Two effects are mainly responsible for the observed enthalpy change in protein unfolding: the disruption of internal interactions within the protein molecule (van der Waals, hydrogen bonds, etc.) and the hydration of the groups that are buried in the native state and become exposed to the solvent on unfolding. In the traditional thermodynamic analysis, the effects of hydration have usually been evaluated using the thermodynamic data for the transfer of small model compounds from the gas phase to water. The contribution of internal interactions, on the other hand, are usually estimated by subtracting the hydration effects from the experimental enthalpy of unfolding. The main drawback of this approach is that the enthalpic contributions of hydration, and those due to the disruption of internal interactions, are more than one order of magnitude larger than the experimental enthalpy value. The enthalpy contributions of hydration and disruption of internal interactions have opposite signs and cancel each other almost completely resulting in a final value that is over 10 times smaller than the individual terms. For this reason, the classical approach cannot be used to accurately predict unfolding enthalpies from structure: any error in the estimation of the hydration enthalpy will be amplified by a factor of 10 or more in the estimation of the unfolding enthalpy. Recently, it has been shown that simple parametric equations that relate the enthalpy change with certain structural parameters, especially changes in solvent accessible surface areas have considerable predictive power. In this paper, we provide a physical foundation to that parametrization and in the process we present a system of equations that explicitly includes the enthalpic effects of the packing density between the different atoms within the protein molecule. Using this approach, the error in the prediction of folding/unfolding enthalpies at 60°C, the median temperature for thermal unfolding, is better than ±3% (standard deviation = 4 kcal/mol). © 1996 Wiley-Liss, Inc.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    The heat capacity of proteins (1995)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 22 (1995), S. 404-412 
    Details
    ISSN: 0887-3585
    Keywords: protein thermodynamics ; protein folding ; protein stability ; protein thermodynamics ; energetics ; protein design ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The heat capacity plays a major role in the determination of the energetics of protein folding and molecular recognition. As such, a better understanding of this thermodynamic parameter and its structural origin will provide new insights for the development of better molecular design strategies. In this paper we have analyzed the absolute heat capacity of proteins in different conformations. The results of these studies indicate that three major terms account for the absolute heat capacity of a protein: (1) one term that depends only on the primary or covalent structure of a protein and contains contributions from vibrational frequencies arising from the stretching and bending modes of each valence bond and internal rotations; (2) a term that contains the contributions of noncovalent interactions arising from secondary and tertiary structure; and (3) a term that contains the contributions of hydration. For a typical globular protein in solution the bulk of the heat capacity at 25°C is given by the covalent structure term (close to 85% of the total). The hydration term contributes about 15 and 40% to the total heat capacity of the native and unfolded states, respectively. The contribution of non-covalent structure to the total heat capacity of the native state is positive but very small and does not amount to more than 3% at 25°C. The change in heat capacity upon unfolding is primarily given by the increase in the hydration term (about 95%) and to a much lesser extent by the loss of noncovalent interactions (up to ∼5%). It is demonstrated that a single universal mathematical function can be used to represent the partial molar heat capacity of the native and unfolded states of proteins in solution. This function can be experimentally written in terms of the molecular weight, the polar and apolar solvent accessible surface areas, and the total area buried from the solvent. This unique function accurately predicts the different magnitude and temperature dependences of the heat capacity of both the native and unfolded states, and therefore of the heat capacity changes associated with folding/unfolding transitions. © 1995 Wiley-Liss, Inc.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340220410
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  • 4
    Electronic Resource
    Electronic Resource
    Structure-based thermodynamic design of peptide ligands: Application to peptide inhibitors of the aspartic protease endothiapepsin (1998)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 30 (1998), S. 74-85 
    Details
    ISSN: 0887-3585
    Keywords: folding and binding ; kinetics ; pepstatin A ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The prediction of binding affinities from structure is a necessary requirement in the development of structure-based molecular design strategies. In this paper, a structural parameterization of the energetics previously developed in this laboratory has been incorporated into a molecular design algorithm aimed at identifying peptide conformations that minimize the Gibbs energy. This approach has been employed in the design of mutants of the aspartic protease inhibitor pepstatin A. The simplest design strategy involves mutation and/or chain length modification of the wild-type peptide inhibitor. The structural parameterization allows evaluation of the contribution of different amino acids to the Gibbs energy in the wild-type structure, and therefore the identification of potential targets for mutation in the original peptide. The structure of the wild-type complex is used as a template to generate families of conformational structures in which specific residues have been mutated. The most probable conformations of the mutated peptides are identified by systematically rotating around the side-chain and backbone torsional angles and calculating the Gibbs potential function of each conformation according to the structural parametrization. The accuracy of this approach has been tested by chemically synthesizing two different mutants of pepstatin A. In one mutant, the alanine at position five has been replaced by a phenylalanine, and in the second one a glutamate has been added at the carboxy terminus of pepstatin A. The thermodynamics of association of pepstatin A and the two mutants have been measured experimentally and the results compared with the predictions. The difference between experimental and predicted Gibbs energies for pepstatin A and the two mutants is 0.23 ± 0.06 kcal/mol. The excellent agreement between experimental and predicted values demonstrates that this approach can be used in the optimization of peptide ligands. Proteins 30:74-85, 1998. © 1998 Wiley-Liss, Inc.
    Additional Material: 7 Ill.
    Type of Medium: Electronic Resource
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