are long-range structural correlations behind the aggregration phenomena of polyglutamine diseases受到多麸醯胺酸是远程aggregration现象背后的结构相关性疾病.pdfVIP

Are Long-Range Structural Correlations Behind the Aggregration Phenomena of Polyglutamine Diseases? Mahmoud Moradi, Volodymyr Babin, Christopher Roland, Celeste Sagui* Center for High Performance Simulations (CHiPS) and Department of Physics, North Carolina State University, Raleigh, North Carolina, United States of America Abstract We have characterized the conformational ensembles of polyglutamine Qn peptides of various lengths n (ranging from 6 to 40), both with and without the presence of a C-terminal polyproline hexapeptide. For this, we used state-of-the-art molecular dynamics simulations combined with a novel statistical analysis to characterize the various properties of the backbone dihedral angles and secondary structural motifs of the glutamine residues. For Q40 (i.e., just above the pathological length ^36 for Huntington’s disease), the equilibrium conformations of the monomer consist primarily of disordered, compact structures with non-negligible a-helical and turn content. We also observed a relatively small population of extended structures suitable for forming aggregates including b- and a-strands, and b- and a-hairpins. Most importantly, for Q40 we find that there exists a long-range correlation (ranging for at least 20 residues) among the backbone dihedral angles of the Q residues. For polyglutamine peptides below the pathological length, the population of the extended strands and hairpins is considerably smaller, and the correlations are short-range (at most 5 residues apart). Adding a C-terminal hexaproline to Q40 suppresses both the population of these rare motifs and the long-range correlation of the dihedral angles. We argue that the long-range correlation of the