Structural variation of alpha-synuclein with temperature by a coarse-grained approach with knowledge-based interactions

Abstract

Despite enormous efforts, our understanding the structure and dynamics of α-synuclein (ASN), a disordered protein (that plays a key role in neurodegenerative disease) is far from complete. In order to better understand sequence-structure-property relationships in α-SYNUCLEIN we have developed a coarse-grained model using knowledge-based residue-residue interactions and used it to study the structure of free ASN as a function of temperature (T) with a large-scale Monte Carlo simulation. Snapshots of the simulation and contour contact maps show changes in structure formation due to self-assembly as a function of temperature. Variations in the residue mobility profiles reveal clear distinction among three segments along the protein sequence. The N-terminal (1-60) and C-terminal (96-140) regions contain the least mobile residues, which are separated by the higher mobility non-amyloid component (NAC) (61-95). Our analysis of the intra-protein contact profile shows a higher frequency of residue aggregation (clumping) in the N-terminal region relative to that in the C-terminal region, with little or no aggregation in the NAC region. The radius of gyration (Rg) of ASN decays monotonically with decreasing the temperature, consistent with the finding of Allison et al. (JACS, 2009). Our analysis of the structure function provides an insight into the mass (N) distribution of ASN, and the dimensionality (D) of the structure as a function of temperature. We find that the globular structure with D ≈ 3 at low T, a random coil, D ≈ 2 at high T and in between (2 ≤ D ≤ 3) at the intermediate temperatures. The magnitudes of D are in agreement with experimental estimates (J. Biological Chem 2002).

Long-range Regulation of Partially Folded Amyloidogenic Peptides

“…S3), employing the smooth Particle Mesh Ewald summation 46 method for obtaining high resolution S(q) values. Several previous studies have estimated the effective dimension of proteins by employing coarse-grain Monte Carlo (MC) simulations to predict changes in structure factor over a range of temperatures, where the wavelength λ was given in MC lattice units [47][48][49] . Here, we applied the B-spline interpolation-based approach for the paired interatomic potential lattice sums generated in our atomistic MD simulations.…”

“…Estimates of −1/γ (annotated alongside plots) reveals D ≈ 1.2 for the fully folded state (CHARMM36/TIP3P) and D ≈ 1 for the fully unfolded state (CHARMM22*/ TIP4P-D), which compares well with the R g . For typical large globular proteins, a value of D ≥ 3 is estimated to be a compact structure, whereas D ≤ 2 is usually a random coil structure [47][48][49] . The effective dimension in both cases for Aβ42 is closer to 2 (than 3) suggesting a random coil-like behaviour which may indicate that Aβ42 is too small (only 42 residues) for accurate estimation of residue distributions with various length scales.…”

Paradoxical Effect of Trehalose on the Aggregation of α-Synuclein: Expedites Onset of Aggregation yet Reduces Fibril Load

“…In the aqueous solution, it exists in numerous extended and compact ensembles of conformations with structures such as random coil, a mechanically weak fold, and a “β-like” state. However, wealth of theoretical ,− and experimental studies ,,, suggests that it prefers to adopt collapsed conformations in water. Thus, amidst the pool of varied conformations, majority of the conformers are in the collapsed states.…”

Preferential binding effects on protein structure and dynamics revealed by coarse-grained Monte Carlo simulation

“…Insights from this comparison will help better understand the spatial fluctuations in preferential binding of solute molecules as a protein unfolds or partially unfolds in a cellular environment or within a liquid formulation. 36,37 The histone H3.1 is an intrinsically disordered protein (IDP) [38][39][40][41][42] that does not have a well-defined tertiary structure in pure water, meaning that it is completely intrinsically disordered. In general, IDPs exhibit a diverse-range of characteristics such as partial unfolding in intrinsically disorder regions, and the degree of disorder can be sensitive to solvent conditions.…”