Turn-Directed α-β Conformational Transition of α-syn12 Peptide at Different pH Revealed by Unbiased Molecular Dynamics Simulations

Lei Liu,Zanxia Cao

doi:10.3390/ijms140610896

Abstract

The transition from α-helical to β-hairpin conformations of α-syn12 peptide is characterized here using long timescale, unbiased molecular dynamics (MD) simulations in explicit solvent models at physiological and acidic pH values. Four independent normal MD trajectories, each 2500 ns, are performed at 300 K using the GROMOS 43A1 force field and SPC water model. The most clustered structures at both pH values are β-hairpin but with different turns and hydrogen bonds. Turn9-6 and four hydrogen bonds (HB9-6, HB6-9, HB11-4 and HB4-11) are formed at physiological pH; turn8-5 and five hydrogen bonds (HB8-5, HB5-8, HB10-3, HB3-10 and HB12-1) are formed at acidic pH. A common folding mechanism is observed: the formation of the turn is always before the formation of the hydrogen bonds, which means the turn is always found to be the major determinant in initiating the transition process. Furthermore, two transition paths are observed at physiological pH. One of the transition paths tends to form the most-clustered turn and improper hydrogen bonds at the beginning, and then form the most-clustered hydrogen bonds. Another transition path tends to form the most-clustered turn, and turn5-2 firstly, followed by the formation of part hydrogen bonds, then turn5-2 is extended and more hydrogen bonds are formed. The transition path at acidic pH is as the same as the first path described at physiological pH.

Highlights

The aggregation of α-synuclein protein in the form of a β-structure is a hallmark of Parkinson’s disease [1,2]
The criterion of clustering is that the conformations are in the same cluster when root-mean-square deviations of Cα positions (RMSDCα) is less than 0.1 nm among the conformations of this cluster
The most clustered structure for the α-syn12 peptide at physiological pH (Figure 1b) is a β-hairpin with Turn9-6 and four hydrogen bonds (HB9-6, HB6-9, HB11-4 and HB4-11); this cluster contains 89% of all the conformations. This structure was consistent with the central structure of the major clusters for the α-syn12 peptide at physiological pH from the temperature replica exchange molecular dynamics (T-REMD) simulations using GROMOS 43A1 force field from our early studies [7]

Summary

Introduction

The aggregation of α-synuclein protein in the form of a β-structure is a hallmark of Parkinson’s disease [1,2]. One is a hydrophobic collapse mechanism [13], where the folding begins from the formation of native hydrophobic clusters, proceeds with the interstrand hydrogen bond. Another is the zipper mechanism [14], the first step of which forms the turn, followed by the formation of interstrand hydrogen bond. Thukrai et al [15,16] investigated the folding mechanism of a 15 residue β-hairpin peptide and found that turn is always the major determinant in initiating the folding process, and supports the second folding mechanism. Yoda et al [17] studied the folding mechanism of a 16 residue peptide of the

Methods

Results

Conclusion