Structural properties of amyloid β(1‐40) dimer explored by replica exchange molecular dynamics simulations

Abstract

Replica exchange molecular dynamics simulations (300 ns) were used to study the dimerization of amyloid β(1-40) (Aβ(1-40)) polypeptide. Configurational entropy calculations revealed that at physiological temperature (310 K, 37°C) dynamic dimers are formed by randomly docked monomers. Free energy of binding of the two chains to each other was -93.56 ± 6.341 kJ mol . Prevalence of random coil conformations was found for both chains with the exceptions of increased β-sheet content from residues 16-21 and 29-32 of chain A and residues 15-21 and 30-33 of chain B with β-turn/β-bend conformations in both chains from residues 1-16, 21-29 of chain A, 1-16, and 21-29 of chain B. There is a mixed β-turn/β-sheet region from residues 33-38 of both chains. Analysis of intra- and interchain residue distances shows that, although the individual chains are highly flexible, the dimer system stays in a loosely packed antiparallel β-sheet configuration with contacts between residues 17-21 of chain A with residues 17-21 and 31-36 of chain B as well as residues 31-36 of chain A with residues 17-21 and 31-36 of chain B. Based on dihedral principal component analysis, the antiparallel β-sheet-loop-β-sheet conformational motif is favored for many low energy sampled conformations. Our results show that Aβ(1-40) can form dynamic dimers in aqueous solution that have significant conformational flexibility and are stabilized by collapse of the central and C-terminal hydrophobic cores with the expected β-sheet-loop-β-sheet conformational motif. Proteins 2017; 85:1024-1045. © 2017 Wiley Periodicals, Inc.

Structural and molecular dynamics of Mycobacterium tuberculosis malic enzyme, a potential anti-TB drug target

“…Domain D, and especially domain C, exhibit the greatest instability; residues in Domain D have RMSF values ranging from 1.5-3.5 Å while domain C has the broadest range from 1-7 Å for the apo MEZ simulation. When compared to RMSF values of other systems, domains C and D are particularly flexible; RMSF values computed from simulations of the highly compact and stable lysozyme are below 1 Å [31], while dimers of Amyloid β(1-40), a highly mobile and flexible protein range from 1-6 Å [33]. Interestingly, though binding might typically be expected to modestly stabilize fluctuations the addition of malate, Mn 2+ and NAD(P) + to the simulations had no impact on the overall stability of the MEZ protein backbone, apart from some reduction in computed αC RMSF values for residues between Gln355 and Ala430 ( Figure S5B).…”

Principal component analysis on a torus: Theory and application to protein dynamics

“…This procedure has been successfully applied to the modeling of biomolecular free energy landscapes. [23][24][25][26][27][28][29][30] There are several cases in which it can be shown that this method yields good results: (1) when the data points are located in the vicinity of some mean value (in which case the approximating affine space will be close to a tangent space of the torus), (2) if the data points are localized in a region which winds around the torus once. In this case a linear space which cuts the torus can be a good approximation.…”

“…However, both methods have their limitations. While dPCA has been shown to represent the energy landscape of biomolecules in high resolution, [23][24][25][26][27][28][29][30] the inherent duplication of coordinates and the nonlinearity of the sine and cosine transformations render it difficult to interpret the results in terms of the underlying observables. In the case of GeoPCA, the description of circular motion as grand circles on hyperdimensional spheres renders it equally difficult to in-terpret the identified principal components.…”

Replica exchange molecular dynamics simulation of the coordination of Pt(ii)-Phenanthroline to amyloid-β

“…REMD is a popular means of improving the reliability and scope of MD simulations, and has been used previously to enhance sampling of possible conformations of the intrinsically disordered Ab peptide. [33][34][35][36][37][38] Application to metal binding to Ab are rare, but one recent study showed how Hamiltonian replica exchange molecular dynamics (H-REMD) enhances sampling of copper-Ab complexes. 39,40 Gaining understanding of how these complexes interact with the Ab peptide may help explain the effect of Ptcoordination on conformational exibility of Ab, and hence provide insight on their anti-AD activity.…”