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Role of backbone solvation in determining thermodynamic beta propensities of the amino acids.

ABSTRACT: There is a paradox concerning the beta propensities of the amino acids: the amino acids with the highest beta propensities such as valine and isoleucine have the highest tendency to desolvate the peptide backbone, which should result in a loss of stability. Nevertheless, backbone solvation, calculated as electrostatic solvation free energy (ESF), is highly correlated with mutant stability in the zinc-finger system studied by Kim and Berg [Kim, C. A. & Berg, J. M. (1993) Nature (London) 362, 267-270], and valine and isoleucine are among the most stabilizing amino acids. This inverse correlation between stability and ESF can be explained, because the mutant ESF differences in the unfolded protein are larger than in the native protein. Consequently, mutations such as Ala to Val destabilize the unfolded form more than the native protein. By comparing mutant Delta ESF values in isolated beta-strands versus beta-sheets, we conclude that amino acids with high beta propensities should exert their stabilizing effects at early stages in folding. This deduction agrees with the studies by Clarke and coworkers [Lorch, M., Mason, J. M., Clarke, A. R. & Parker, M. J. (1999) Biochemistry 38, 1377-1385, and Lorch, M., Mason, J. M., Sessions, R. B. & Clarke, A. R. (2000) Biochemistry 39, 3480-3485] of the thermodynamics of folding of the beta-sheet protein CD2.d1.

SUBMITTER: Avbelj F

PROVIDER: S-EPMC122186 | biostudies-literature | 2002 Feb

REPOSITORIES: biostudies-literature

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Role of backbone solvation in determining thermodynamic beta propensities of the amino acids.

Avbelj Franc F Baldwin Robert L RL

Proceedings of the National Academy of Sciences of the United States of America 20020122 3

There is a paradox concerning the beta propensities of the amino acids: the amino acids with the highest beta propensities such as valine and isoleucine have the highest tendency to desolvate the peptide backbone, which should result in a loss of stability. Nevertheless, backbone solvation, calculated as electrostatic solvation free energy (ESF), is highly correlated with mutant stability in the zinc-finger system studied by Kim and Berg [Kim, C. A. & Berg, J. M. (1993) Nature (London) 362, 267- ...[more]

PMID: 11805303

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Project description:An amino acid sequence, in the context of the solvent environment, contains all of the thermodynamic information necessary to encode a three-dimensional protein structure. To investigate the relationship between an amino acid sequence and its corresponding protein fold, a database of thermodynamic stability information was assembled that spanned 2951 residues from 44 nonhomologous proteins. This information was obtained using the COREX algorithm, which computes an ensemble-based description of the native state of a protein. It was observed that amino acid types partitioned unequally into high, medium, and low thermodynamic stability environments. Furthermore, these distributions were reproducible and were significantly different than those expected from random partitioning. To assess the structural importance of the distributions, simple fold-recognition experiments were performed based on a 3D-1D scoring matrix containing only COREX residue stability information. This procedure was able to recover amino acid sequences corresponding to correct target structures more effectively than scoring matrices derived from randomized data. High-scoring sequences were often aligned correctly with their corresponding target profiles, suggesting that calculated thermodynamic stability profiles have the potential to encode sequence information. As a control, identical fold-recognition experiments were performed on the same database of proteins using DSSP secondary structure information in the scoring matrix, instead of COREX residue stability information. The comparable performance of both approaches suggested that COREX residue stability information and secondary structure information could be of equivalent utility in more sophisticated fold-recognition techniques. The results of this work are a consequence of the idea that amino acid sequences fold not into single, rigidly stable structures but rather into thermodynamic ensembles best represented by a time-averaged structure.

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Role of backbone solvation in determining thermodynamic beta propensities of the amino acids.

Publications

Role of backbone solvation in determining thermodynamic beta propensities of the amino acids.

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