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Configurational entropy elucidates the role of salt-bridge networks in protein thermostability.

ABSTRACT: Detailed knowledge of how networks of surface salt bridges contribute to protein thermal stability is essential not only to understand protein structure and function but also to design thermostable proteins for industrial applications. Experimental studies investigating thermodynamic stability through measurements of free energy associated with mutational alterations in proteins provide only macroscopic evidence regarding the structure of salt-bridge networks and assessment of their contribution to protein stability. Using explicit-solvent molecular dynamics simulations to provide insight on the atomic scale, we investigate here the structural stability, defined in terms of root-mean-square fluctuations, of a short polypeptide designed to fold into a stable trimeric coiled coil with a well-packed hydrophobic core and an optimal number of intra- and interhelical surface salt bridges. We find that the increase of configurational entropy of the backbone and side-chain atoms and decreased pair correlations of these with increased temperature are consistent with nearly constant atom-positional root-mean-square fluctuations, increased salt-bridge occupancies, and stronger electrostatic interactions in the coiled coil. Thus, our study of the coiled coil suggests a mechanism in which well-designed salt-bridge networks could accommodate stochastically the disorder of increased thermal motion to produce thermostability.

SUBMITTER: Missimer JH

PROVIDER: S-EPMC2206687 | biostudies-literature | 2007 Jul

REPOSITORIES: biostudies-literature

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Configurational entropy elucidates the role of salt-bridge networks in protein thermostability.

Missimer John H JH Steinmetz Michel O MO Baron Riccardo R Winkler Fritz K FK Kammerer Richard A RA Daura Xavier X van Gunsteren Wilfred F WF

Protein science : a publication of the Protein Society 20070701 7

Detailed knowledge of how networks of surface salt bridges contribute to protein thermal stability is essential not only to understand protein structure and function but also to design thermostable proteins for industrial applications. Experimental studies investigating thermodynamic stability through measurements of free energy associated with mutational alterations in proteins provide only macroscopic evidence regarding the structure of salt-bridge networks and assessment of their contribution ...[more]

PMID: 17586770

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Project description:The recently developed NMR techniques enable estimation of protein configurational entropy change from the change in the average methyl order parameters. This experimental observable, however, does not directly measure the contribution of intramolecular couplings, protein main-chain motions, or angular dynamics. Here, we carry out a self-consistent computational analysis of the impact of these missing contributions on an extensive set of molecular dynamics simulations of different proteins undergoing binding. Specifically, we compare the configurational entropy change in protein complex formation as obtained by the maximum information spanning tree approximation (MIST), which treats the above entropy contributions directly, and the change in the average NMR methyl and NH order parameters. Our parallel implementation of MIST allows us to treat hard angular degrees of freedom as well as couplings up to full pairwise order explicitly, while still involving a high degree of sampling and tackling molecules of biologically relevant sizes. First, we demonstrate a remarkably strong linear relationship between the total configurational entropy change and the average change in both methyl and backbone-NH order parameters. Second, in contrast to canonical assumptions, we show that the main-chain and angular terms contribute significantly to the overall configurational entropy change and also scale linearly with it. Consequently, linear models starting from the average methyl order parameters are able to capture the contribution of main-chain and angular terms well. After applying the quantum-mechanical harmonic oscillator entropy formalism, we establish a similarly strong linear relationship for X-ray crystallographic B-factors. Finally, we demonstrate that the observed linear relationships remain robust against drastic undersampling and argue that they reflect an intrinsic property of compact proteins. Despite their remarkable strength, however, the above linear relationships yield estimates of configurational entropy change whose accuracy appears to be sufficient for qualitative applications only.

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Configurational entropy elucidates the role of salt-bridge networks in protein thermostability.

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Configurational entropy elucidates the role of salt-bridge networks in protein thermostability.

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