Park Jiyong, Kahng Byungnam, Hwang Wonmuk
Department of Physics and Astronomy, Seoul National University, Seoul, Korea.
PLoS Comput Biol. 2009 Sep;5(9):e1000492. doi: 10.1371/journal.pcbi.1000492. Epub 2009 Sep 4.
At the core of amyloid fibrils is the cross-beta spine, a long tape of beta-sheets formed by the constituent proteins. Recent high-resolution x-ray studies show that the unit of this filamentous structure is a beta-sheet bilayer with side chains within the bilayer forming a tightly interdigitating "steric zipper" interface. However, for a given peptide, different bilayer patterns are possible, and no quantitative explanation exists regarding which pattern is selected or under what condition there can be more than one pattern observed, exhibiting molecular polymorphism. We address the structural selection mechanism by performing molecular dynamics simulations to calculate the free energy of incorporating a peptide monomer into a beta-sheet bilayer. We test filaments formed by several types of peptides including GNNQQNY, NNQQ, VEALYL, KLVFFAE and STVIIE, and find that the patterns with the lowest binding free energy correspond to available atomistic structures with high accuracy. Molecular polymorphism, as exhibited by NNQQ, is likely because there are more than one most stable structures whose binding free energies differ by less than the thermal energy. Detailed analysis of individual energy terms reveals that these short peptides are not strained nor do they lose much conformational entropy upon incorporating into a beta-sheet bilayer. The selection of a bilayer pattern is determined mainly by the van der Waals and hydrophobic forces as a quantitative measure of shape complementarity among side chains between the beta-sheets. The requirement for self-complementary steric zipper formation supports that amyloid fibrils form more easily among similar or same sequences, and it also makes parallel beta-sheets generally preferred over anti-parallel ones. But the presence of charged side chains appears to kinetically drive anti-parallel beta-sheets to form at early stages of assembly, after which the bilayer formation is likely driven by energetics.
淀粉样纤维的核心是交叉β链，它是由组成蛋白形成的β折叠片层的长带。最近的高分辨率X射线研究表明，这种丝状结构的单元是一个β折叠片层双层，双层内的侧链形成紧密交错的“空间拉链”界面。然而，对于给定的肽，可能存在不同的双层模式，并且对于选择哪种模式或在何种条件下可以观察到不止一种模式（即表现出分子多态性），目前尚无定量解释。我们通过进行分子动力学模拟来计算将肽单体纳入β折叠片层双层的自由能，从而解决结构选择机制问题。我们测试了由几种类型的肽形成的纤维，包括GNNQQNY、NNQQ、VEALYL、KLVFFAE和STVIIE，发现具有最低结合自由能的模式与可用的原子结构高度吻合。NNQQ所表现出的分子多态性可能是因为存在不止一种最稳定的结构，其结合自由能的差异小于热能。对各个能量项的详细分析表明，这些短肽在纳入β折叠片层双层时既没有应变，也没有损失太多构象熵。双层模式的选择主要由范德华力和疏水力决定，这是β折叠片层之间侧链形状互补性的定量度量。对自互补空间拉链形成的要求支持了淀粉样纤维在相似或相同序列之间更容易形成的观点，并且这也使得平行β折叠片层通常比反平行β折叠片层更受青睐。但是带电侧链的存在似乎在动力学上驱动反平行β折叠片层在组装的早期阶段形成，在此之后双层的形成可能由能量学驱动。
