The molecular dynamics of assembly of the ubiquitous aortic medial amyloidal medin fragment

被引:7
作者
Gazit, Ehud
della Bruna, Paola
Pieraccini, Stefano
Colombo, Giorgio
机构
[1] CNR, Ist Chim Riconoscimento Mol, I-20131 Milan, Italy
[2] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Mol Microbiol & Biotechnol, IL-69978 Tel Aviv, Israel
关键词
amyloid fibril formation; molecular dynamics; aortic medial amyloid; aromatic interaction; molecular recognition; protein misfolding; self-assembly;
D O I
10.1016/j.jmgm.2006.09.001
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
In recent years there is an increased understanding of the molecular conformation of amyloid fibrils. However, much less is known about the early events that lead to the formation of these medically important assemblies. The clarification of these very important mechanistic details on the process may indicate directions towards the inhibition of the early stages of the assembly, where harmful species are most likely to form. Here, we study the dynamics of assembly of short amyloidogenic peptide fragments from the medin polypeptide. This polypeptide is of unique interest since amyloid deposits composed of medin are found almost in all the population above the age of 50. Twelve independent 50 ns long molecular dynamics simulations in explicit water have been run on peptide NH2-NFGSVQFV-COOH, the minimal recognition hexapeptide element, NH2-NFGSVQ-COOH, and several single-point mutants. In all cases a three-stranded polymeric P-sheet was used as the basic unit from which fibrils can be formed. Our results clearly indicate the need of well-defined sequence and stereochemical constraints to allow the formation of stable well-ordered aggregates. One of the key findings is the need for the presence of a phenylalanine residue, but not other hydrophobic amino acids, in specific positions within the peptide. Taken together, the results are consistent with recent high-resolution structures of amyloid assemblies and provide unique insights into the dynamics of these structures. (c) 2006 Elsevier Inc. All rights reserved.
引用
收藏
页码:903 / 911
页数:9
相关论文
共 46 条
[41]   Inhibition of heparin-induced tau filament formation by phenothiazines, polyphenols, and porphyrins [J].
Taniguchi, S ;
Suzuki, N ;
Masuda, M ;
Hisanaga, S ;
Iwatsubo, T ;
Goedert, M ;
Hasegawa, M .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (09) :7614-7623
[42]   Prediction of aggregation rate and aggregation-prone segments in polypeptide sequences [J].
Tartaglia, GG ;
Cavalli, A ;
Pellarin, R ;
Caflisch, A .
PROTEIN SCIENCE, 2005, 14 (10) :2723-2734
[43]  
van Gunsteren W.F., 2002, Encyclopedia of Computational Chemistry, DOI DOI 10.1002/0470845015.CGA011
[44]   Side chain interactions determine the amyloid organization:: a single layer β-sheet molecular structure of the calcitonin peptide segment 15-19 [J].
Zanuy, D ;
Haspel, N ;
Tsai, HH ;
Ma, BY ;
Gunasekaran, K ;
Wolfson, HJ ;
Nussinov, R .
PHYSICAL BIOLOGY, 2004, 1 (1-2) :89-99
[45]   The sequence dependence of fiber organization. A comparative molecular dynamics study of the islet amyloid polypeptide segments 22-27 and 22-29 [J].
Zanuy, D ;
Nussinov, R .
JOURNAL OF MOLECULAR BIOLOGY, 2003, 329 (03) :565-584
[46]   Peptide sequence and amyloid formation: Molecular simulations and experimental study of a human islet amyloid polypeptide fragment and its analogs [J].
Zanuy, D ;
Porat, Y ;
Gazit, E ;
Nussinov, R .
STRUCTURE, 2004, 12 (03) :439-455