Alterations of Nonconserved Residues Affect Protein Stability and Folding Dynamics through Charge鈥揅harge Interactions

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• 作者：Swarnendu Tripathi ; Angel E. Garc矛a ; George I. Makhatadze
• 刊名：Journal of Physical Chemistry B
• 出版年：2015
• 出版时间：October 15, 2015
• 年：2015
• 卷：119
• 期：41
• 页码：13103-13112
• 全文大小：632K
• ISSN：1520-5207

文摘

Charge鈥揷harge interactions play an important role in thermal stability of proteins. We employed an all-atom, native-topology-based model with non-native electrostatics to explore the interplay between folding dynamics and stability of TNfn3 (the third fibronectin type III domain from tenascin-C). Our study elucidates the role of charge鈥揷harge interactions in modulating the folding energy landscape. In particular, we found that incorporation of explicit charge鈥揷harge interactions in the WT TNfn3 induces energetic frustration due to the presence of residual structure in the unfolded state. Moreover, optimization of the surface charge鈥揷harge interactions by altering the evolutionarily nonconserved residues not only increases the thermal stability (in agreement with previous experimental study) but also reduces the formation of residual structure and hence minimizes the energetic frustration along the folding route. We concluded that charge鈥揷harge interaction in the rationally designed TNfn3 plays an important role not only in enhancing the stability but also in assisting folding.