Strodel Birgit, Whittleston Chris S, Wales David J
University Chemical Laboratories, Lensfield Road, Cambridge CB2 1EW, UK.
J Am Chem Soc. 2007 Dec 26;129(51):16005-14. doi: 10.1021/ja075346p. Epub 2007 Dec 4.
The energy landscape of the monomer and dimer are explored for the amyloidogenic heptapeptide GNNQQNY from the N-terminal prion-determining domain of the yeast protein Sup35. The peptide is modeled by a united-atom potential and an implicit solvent representation. Replica exchange molecular dynamics is used to explore the conformational space, and discrete path sampling is employed to investigate the pathways that interconvert the most populated minima on the free energy surfaces. For the monomer, we find a rapid fluctuation between four different conformations, where a geometry intermediate between compact and extended structures is the most thermodynamically favorable. The GNNQQNY dimer forms three stable sheet structures, namely in-register parallel, off-register parallel, and antiparallel. The antiparallel dimer is stabilized by strong electrostatic interactions resulting from interpeptide hydrogen bonds, which restrict its conformational flexibility. The in-register parallel dimer, which is close to the amyloid beta-sheet structure, has fewer interpeptide hydrogen bonds, making hydrophobic interactions more important and increasing the conformational entropy compared to the antiparallel sheet. The estimated two-state rate constants indicate that the formation of dimers from monomers is fast and that the dimers are kinetically stable against dissociation at room temperature. Interconversions between the different dimers are feasible processes and are more likely than dissociation.
我们从酵母蛋白Sup35的N端朊病毒决定域出发，对淀粉样生成七肽GNNQQNY的单体和二聚体的能量景观进行了探索。该肽通过联合原子势和隐式溶剂表示进行建模。采用副本交换分子动力学来探索构象空间，并使用离散路径采样来研究在自由能面上相互转换最丰富极小值的途径。对于单体，我们发现它在四种不同构象之间快速波动，其中一种介于紧密结构和伸展结构之间的几何结构在热力学上最有利。GNNQQNY二聚体形成三种稳定的片层结构，即同向平行、错向平行和反平行。反平行二聚体通过肽间氢键产生的强静电相互作用而稳定，这限制了其构象灵活性。与反平行片层相比，接近淀粉样β片层结构的同向平行二聚体的肽间氢键较少，使得疏水相互作用更为重要，并增加了构象熵。估计的双态速率常数表明，单体形成二聚体的过程很快，并且二聚体在室温下动力学上对解离是稳定的。不同二聚体之间的相互转换是可行的过程，并且比解离更有可能发生。
