Nikiforovich Gregory V, Andersen Niels H, Fesinmeyer R Matthew, Frieden Carl
Department of Biochemistry and Molecular Biophysics, Washington University, St. Louis, Missouri 63110, USA.
Proteins. 2003 Aug 1;52(2):292-302. doi: 10.1002/prot.10409.
A novel computational procedure for modeling possible locally driven folding pathways by stepwise elongations of the peptide chain was successfully applied to TC5b, a 20-residue miniprotein. Systematic exploration of the possible locally driven pathways showed that the Trp-cage structure of TC5b could be obtained by stepwise elongation starting from the noncentral local nucleation centers preexisting in the unfolded state of TC5b. The probable locally driven folding pathway starts with folding of alpha-helical fragment 4-9, followed by formation of the proper three-dimensional structure of fragment 4-12, and then 4-18. Accordingly, the Trp-cage-forming interactions emerge successively, first Trp(6)-Pro(12), then Trp(6)-Pro(18), and then Trp(6)-Tyr(3). The Trp-cage-like structures of TC5b found in this study by independent energy calculations are in excellent agreement with the NMR experimental data. The same procedure rationalizes the incomplete Trp-cage formation observed for two analogs of TC5b. Generally, the success of this novel approach is encouraging and provides some justification for the use of computational simulations of locally driven protein folding.
一种通过肽链逐步延伸来模拟可能的局部驱动折叠途径的新型计算程序已成功应用于TC5b（一种由20个残基组成的微型蛋白质）。对可能的局部驱动途径的系统探索表明，TC5b的色氨酸笼结构可以从TC5b未折叠状态中预先存在的非中心局部成核中心开始逐步延伸获得。可能的局部驱动折叠途径始于α-螺旋片段4-9的折叠，接着是片段4-12形成适当的三维结构，然后是4-18。相应地，形成色氨酸笼的相互作用相继出现，首先是Trp(6)-Pro(12)，然后是Trp(6)-Pro(18)，接着是Trp(6)-Tyr(3)。本研究通过独立能量计算发现的TC5b的类色氨酸笼结构与NMR实验数据高度吻合。相同的程序解释了在TC5b的两个类似物中观察到的不完全色氨酸笼形成现象。总体而言，这种新方法的成功令人鼓舞，并为使用局部驱动蛋白质折叠的计算模拟提供了一些依据。
