Dataset Information

Initial Structural Models of the A?42 Dimer from Replica Exchange Molecular Dynamics Simulations.

ABSTRACT: Experimental characterization of the molecular structure of small amyloid (A)? oligomers that are currently considered as toxic agents in Alzheimer's disease is a formidably difficult task due to their transient nature and tendency to aggregate. Such structural information is of importance because it can help in developing diagnostics and an effective therapy for the disease. In this study, molecular simulations and protein-protein docking are employed to explore a possible connection between the structure of A? monomers and the properties of the intermonomer interface in the A?42 dimer. A structurally diverse ensemble of conformations of the monomer was sampled in microsecond timescale implicit solvent replica exchange molecular dynamics simulations. Representative structures with different solvent exposure of hydrophobic residues and secondary structure content were selected to build structural models of the dimer. Analysis of these models reveals that formation of an intramonomer salt bridge (SB) between Asp23 and Lys28 residues can prevent the building of a hydrophobic interface between the central hydrophobic clusters (CHCs) of monomers upon dimerization. This structural feature of the A?42 dimer is related to the difference in packing of hydrophobic residues in monomers with the Asp23-Lys28 SB in on and off states, in particular, to a lower propensity to form hydrophobic contacts between the CHC domain and C-terminal residues in monomers with a formed SB. These findings could have important implications for understanding the difference between aggregation pathways of A? monomers leading to neurotoxic oligomers or inert fibrillar structures.

SUBMITTER: Blinov N

PROVIDER: S-EPMC6645216 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Initial Structural Models of the Aβ42 Dimer from Replica Exchange Molecular Dynamics Simulations.

Blinov Nikolay N Khorvash Massih M Wishart David S DS Cashman Neil R NR Kovalenko Andriy A

ACS omega 20171107 11

Experimental characterization of the molecular structure of small amyloid (A)β oligomers that are currently considered as toxic agents in Alzheimer's disease is a formidably difficult task due to their transient nature and tendency to aggregate. Such structural information is of importance because it can help in developing diagnostics and an effective therapy for the disease. In this study, molecular simulations and protein-protein docking are employed to explore a possible connection between th ...[more]

PMID: 31457321

Similar Datasets

Project description:Levan has various potential applications in the pharmaceutical and food industries, such as cholesterol-lowering agents and prebiotics, due to its beneficial properties, which depend on its length and branching degree. A previous study also found that the branching degree of levan affected anti-tumor activities against SNU-1 and HepG2 tumor cell lines. Despite its promising potential, the properties of levans with different branching degrees are not well understood at the molecular level. In two models of the generalized Born implicit solvent (GBHCT and GBOBC1), we employed replica-exchange molecular dynamics simulations to explore conformational spaces of 34-residue levans (L34) with branching degrees of zero (LFO34B0), one (LFO34B1), three (LFO34B3) and five (LFO34B5), as well as to elucidate their structural and molecular properties. To ensure a fair comparison of the effects of branching degree on these properties, we focused on analyzing the properties of the central 21-residue of the main chains of all systems. Our results show that all major representative conformations tend to form helix-like structures with kinks, where two-kink helix-like structures have the highest population. As branching degree increases, the population of helix-like structures with zero or one kink tends to increase slightly. As the number of kinks in the structures with the same branching degree increases, the average values of the lengths and angles among centers of masses of three consecutive turns of residue i, i+3, and i+6 tended to decrease. Due to its highest occurring frequencies, the O6 (i)-H3O (i+1) hydrogen bond could be important for helix-like structure formation. Moreover, hydrogen bonds forming among the branching residue (br), branching position (bp) and other residues of L34B1, L34B3 and L34B5 were identified. The O1(bp)-H3O(br), O1(br)-H3O(br) and O5(br)-H1O(br) hydrogen bonds were found in the first-, second- and third-highest occurrence frequencies, respectively. Our study provides novel and important insights into conformational spaces and the structural and molecular properties of 34-residue levans with various branching degrees, which tend to form helix-like structures with kinks.

Dataset Information

Initial Structural Models of the A?42 Dimer from Replica Exchange Molecular Dynamics Simulations.

Publications

Initial Structural Models of the Aβ42 Dimer from Replica Exchange Molecular Dynamics Simulations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets