unfolding of the amyloid β-peptide central helix mechanistic insights from molecular dynamics simulations展开的淀粉样蛋白β-peptide中央螺旋机械的见解从分子动力学模拟.pdfVIP

Unfolding of the Amyloid b-Peptide Central Helix: Mechanistic Insights from Molecular Dynamics Simulations 1 2,3 ¨ 1 1 Mika Ito , Jan Johansson , Roger Stromberg , Lennart Nilsson * 1 Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden, 2 Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, the Biomedical Centre, Uppsala, Sweden, 3 Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet Alzheimer Disease Research Center (KI-ADRC), Huddinge, Sweden Abstract Alzheimer’s disease (AD) pathogenesis is associated with formation of amyloid fibrils caused by polymerization of the amyloid b-peptide (Ab), which is a process that requires unfolding of the native helical structure of A b. According to recent experimental studies, stabilization of the Ab central helix is effective in preventing Ab polymerization into toxic assemblies. To uncover the fundamental mechanism of unfolding of the A b central helix, we performed molecular dynamics simulations for wild-type (WT), V18A/F19A/F20A mutant (MA), and V18L/F19L/F20L mutant (ML) models of the A b central helix. It was quantitatively demonstrated that the stability of the a-helical conformation of both MA and ML is higher than that of WT, indicating that the a-helical propensity of the three nonpolar residues (18, 19, and 20) is the main factor for the stability of the whole A b central helix and that their hydrophobicity plays a secondary role. WT was found to completely unfold by a three-step mechanism: 1) loss of a-helical backbone hydrogen bonds, 2) strong interactions between nonpolar sidechains, and 3) strong interactions between polar