Ma Buyong, Nussinov Ruth
Basic Research Program, SAIC-Frederick, Inc, Laboratory of Experimental and Computational Biology, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.
Protein Sci. 2003 Sep;12(9):1882-93. doi: 10.1110/ps.0306103.
We have investigated free energy landscape [MM/PBSA + normal modes entropy] of permutations in the G peptide (41-56) from the protein G B1 domain by studying six isomers corresponding to moving the hydrophobic cluster along the beta-strands (toward the turn: T1, AGEWTYDDKTFTVTET; T2, GEDTWDYATFTVTKTE; T3, GEDDWTYATFTVTKTE; toward the end: E1, WTYDDAGETKTFTVT; E2, WEYTGDDATKTETFTV; E3, WTYEGDDATKTETFTV). The free energy terms include molecular mechanics energy, Poisson-Boltzmann electrostatic solvation energy, surface area solvation energy, and conformational entropy estimated by using normal mode analysis. From the wild type to T1, then T3, and finally T2, we see a progressively changing energy landscape, toward a less stable beta-hairpin structure. Moving the hydrophobic cluster outside toward the end region causes a greater change in the energy landscape. alpha-Helical instead of a beta-hairpin structure was the most stable form for the E2 isomer. However, no matter how much the sequence changes, for all variants studied, ideal "native" beta-hairpin topologies remain as minima (regardless of whether global or local) in the energy landscape. In general, we find that the energy landscape is dependent on the hydrophobic cluster topology and on the sequence. Our present study indicates that the key is the relative conformational energies of the different conformations. Changes in the sequence strongly modulate the relative stabilities of topologically similar regions in the energy landscape, rather than redefine the topology space. This finding is consistent with a population redistribution in the process of protein folding. The limited variation of topological space, compared with the number of possible sequence changes, may relate to the observation that the number of known protein folds are far less than the sequential allowance.
我们通过研究与沿β链移动疏水簇相对应的六种异构体（朝向转角：T1，AGEWTYDDKTFTVTET；T2，GEDTWDYATFTVTKTE；T3，GEDDWTYATFTVTKTE；朝向末端：E1，WTYDDAGETKTFTVT；E2，WEYTGDDATKTETFTV；E3，WTYEGDDATKTETFTV），研究了来自G蛋白B1结构域的G肽（41 - 56）中排列的自由能景观[MM/PBSA + 简正模式熵]。自由能项包括分子力学能量、泊松 - 玻尔兹曼静电溶剂化能、表面积溶剂化能以及通过简正模式分析估计的构象熵。从野生型到T1，再到T3，最后到T2，我们看到能量景观逐渐变化，朝着稳定性较低的β - 发夹结构发展。将疏水簇移向末端区域会导致能量景观发生更大变化。对于E2异构体，α - 螺旋而非β - 发夹结构是最稳定的形式。然而，无论序列如何变化，对于所有研究的变体，理想的“天然”β - 发夹拓扑结构在能量景观中仍作为最小值（无论全局还是局部）存在。总体而言，我们发现能量景观取决于疏水簇拓扑结构和序列。我们目前的研究表明，关键在于不同构象的相对构象能量。序列变化强烈调节能量景观中拓扑相似区域的相对稳定性，而不是重新定义拓扑空间。这一发现与蛋白质折叠过程中的群体重新分布一致。与可能的序列变化数量相比，拓扑空间的有限变化可能与已知蛋白质折叠数量远少于序列允许数量的观察结果有关。
