Context and Force Field Dependence of the Loss of Protein Backbone Entropy upon Folding Using Realistic Denatured and Native State Ensembles

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• 作者：Michael C. Baxa ; Esmael J. Haddadian ; Abhishek K. Jha ; Karl F. Freed ; Tobin R. Sosnick
• 刊名：The Journal of the American Chemical Society
• 出版年：2012
• 出版时间：September 26, 2012
• 年：2012
• 卷：134
• 期：38
• 页码：15929-15936
• 全文大小：532K
• 年卷期：v.134,no.38(September 26, 2012)
• ISSN：1520-5126

文摘

The loss of conformational entropy is the largest unfavorable quantity affecting a protein鈥檚 stability. We calculate the reduction in the number of backbone conformations upon folding using the distribution of backbone dihedral angles (,蠄) obtained from an experimentally validated denatured state model, along with all-atom simulations for both the denatured and native states. The average loss of entropy per residue is T螖S^BB_U鈥揘 = 0.7, 0.9, or 1.1 kcal路mol^鈥? at T = 298 K, depending on the force field used, with a 0.6 kcal路mol^鈥? dispersion across the sequence. The average equates to a decrease of a factor of 3鈥? in the number of conformations available per residue (f = 惟_Denatured/惟_Native) or to a total of f_tot = 3ⁿ鈥?ⁿ for an n residue protein. Our value is smaller than most previous estimates where f = 7鈥?0, that is, our computed T螖S^BB_U鈥揘 is smaller by 10鈥?00 kcal mol^鈥? for n = 100. The differences emerge from our use of realistic native and denatured state ensembles as well as from the inclusion of accurate local sequence preferences, neighbor effects, and correlated motions (vibrations), in contrast to some previous studies that invoke gross assumptions about the entropy in either or both states. We find that the loss of entropy primarily depends on the local environment and less on properties of the native state, with the exception of 伪-helical residues in some force fields.