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Understanding the determinants of stability and folding of small globular proteins from their energetics

¹ Department of Physics, University of Milano, 20133 Milano, Italy
² Istituto Nazionale Fisica Nucleare (INFN), 20133 Milano, Italy
³ Istituto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Richerche (CNR), 20131 Milano, Italy
⁴ The Niels Bohr Institute, 2100 Copenhagen, Denmark

Reprint requests to: G. Colombo, Istituto di Chimica del Riconoscimento Molecolare, CNR, via Mario Bianco 9, 20131 Milano, Italy; e-mail: giorgio. colombo{at}icrm.cnr.it; fax: 39-02-28500036.

The results of minimal model calculations indicate that the stability and the kinetic accessibility of the native state of small globular proteins are controlled by few "hot" sites. By means of molecular dynamics simulations around the native conformation, which describe the protein and the surrounding solvent at the all-atom level, an accurate and compact energetic map of the native state of the protein is generated. This map is further simplified by means of an eigenvalue decomposition. The components of the eigenvector associated with the lowest eigenvalue indicate which hot sites are likely to be responsible for the stability and for the rapid folding of the protein. The comparison of the results of the model with the findings of mutagenesis experiments performed for four small proteins show that the eigenvalue decomposition method is able to identify between 60% and 80% of these (hot) sites.

Keywords: protein folding; protein stability; molecular dynamics; local elementary structures

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