Maximiano, P. | Search bioRxiv

bioRxiv2026

Beyond Co-Existence: α-Synuclein Sequesters Amyloid-β42 into Distinct Hybrid Assemblies

Amyloid-{beta} (A{beta}) deposits often appear in Parkinson's disease and -synuclein (-syn) pathology in Alzheimer's disease. As soluble oligomers contribute importantly to cytotoxicity, their early crosstalk is critical to understand. Using all-atom molecular dynamics, we investigated how the initial oligomeric configuration of A{beta}42 shapes its early association with -syn, simulating -syn with (i) one A{beta}42 monomer, (ii) two separated monomers, and (iii) a pre-formed dimer plus a free monomer, across 15 independent 3 s trajectories. Association patterns depended strongly on the initial configuration. With monomeric or nascent dimeric A{beta}42, -syn frequently contacted the metal-binding, central hydrophobic core (CHC), and C-terminal regions, and these contacts were temporally coordinated, most reproducibly the -syn NAC with the A{beta}42 CHC and polar regions. {beta}-hairpin sampling was reduced specifically when -syn engaged the CHC and C-terminus, an interface-dependent rather than a general effect that did not track contact duration, and coincided with more expanded conformations. With a pre-formed dimer, -syn associated mainly peripherally, while the dimer's {beta}-structured interface remained comparatively stable. First-order dihedral entropy differed only modestly between the free and associated states, indicating that association redistributed conformational populations without globally reducing local backbone diversity. Overall, -syn's early structural effect on A{beta}42 is configuration-dependent: it engages and perturbs lower-order species while associating only peripherally with the sampled dimer.

biochemistry↗

bioRxiv2026

Bigger Isn't Always Better: Comparing System Size, Hydration, and Software for Lipid Membrane Analysis

The structural and dynamic properties of membranes are known to vary with bilayer size and hydration. While Molecular Dynamic (MD) simulations are a powerful tool for studying cellular membrane systems, the results can be sensitive to the analysis work-flow and software. In this study, all-atom MD simulations (500 ns) were conducted on systems of 256, 512, and 1024 POPC lipids at 40, 80, and 160 waters per lipid. With these simulations, a two-fold study was performed: (1) to assess the convergence of structural and dynamic properties of POPC bilayers as a function of membrane size and hydration level using CPPTRAJ (CPP), including area per lipid (APL), bilayer thickness, order parameter, headgroup orientation, and lateral diffusion, and (2) to compare the analysis output and performance of four software packages: CPP, GROMACS (GRO), MDAnalysis (MDA), and LiPyphilic (LiP). For the first objective, our results show that the average values of the bilayer thickness, order parameter, and headgroup orientation are largely independent of the size and hydration levels studied. In contrast, lateral diffusion coefficient was sensitive to both size and hydration. We found that increasing the system size primarily decreased the statistical variance of the APL and thickness. For the second objective, all four packages produced consistent results for APL and thickness, with the most significant discrepancy being a known artifact from the gmx order tool when applied to unsaturated carbons. Performance bench-marks identified CPP as the fastest serial tool for all properties, whereas parallelization benefited MDA and LiP in some metrics. These findings provide a practical roadmap, demonstrating that moderately sized systems (e.g., 256L), combined with an optimized tool such as CPP, offer an efficient workflow for membrane structural property analysis.

biophysics↗