Dynamics of Seeded Aβ₄₀-Fibril Growth from Atomistic Molecular Dynamics Simulations: Kinetic Trapping and Reduced Water Mobility in the Locking Step

Abstract

Filamentous β-amyloid aggregates are crucial for the pathology of Alzheimer's disease. Despite the tremendous biomedical importance, the molecular pathway of growth propagation is not completely understood and remains challenging to investigate by simulations due to the long time scales involved. Here, we apply extensive all-atom molecular dynamics simulations in explicit water to obtain free energy profiles and kinetic information from position-dependent diffusion profiles for three different Aβ9-40-growth processes: fibril elongation by single monomers at the structurally unequal filament tips and association of larger filament fragments. Our approach provides insight into the molecular steps of the kinetic pathway and allows close agreement with experimental binding free energies and macroscopic growth rates. Water plays a decisive role, and solvent entropy is identified as the main driving force for assembly. Fibril growth is disfavored energetically due to cancellation of direct peptide-peptide interactions and solvation effects. The kinetics of growth is consistent with the characteristic dock/lock mechanism, and docking is at least 2 orders of magnitude faster. During initial docking, interactions are mediated by transient non-native hydrogen bonds, which efficiently catch the incoming monomer or fragment already at separations of about 3 nm. In subsequent locking, the dynamics is much slower due to formation of kinetically trapped conformations caused by long-lived non-native hydrogen bonds. Fibril growth additionally requires collective motion of water molecules to create a dry binding interface. Fibril growth is further retarded due to reduced mobility of the involved hydration water, evident from a 2-fold reduction of the diffusion coefficient.

Energy Decomposition Analysis Based on Absolutely Localized Molecular Orbitals for Large-Scale Density Functional Theory Calculations in Drug Design

“…Intuitively, a more favourable ∆E FRZ component is expected for the water -ammonium system due to the strong electrostatic interaction of the charged ammonium molecule with the dipole of the water molecule. Our expectations are confirmed by assessment of the electrostatic energy: for this system we observe electrostatic contributions of -25.3 kcal/mol and -25.5 kcal/mol through the ONETEP and LMO EDAs respec- 1 For all calculations excluding the benzene -ammonium system the polarisation stage NGWFs were initialised to the converged fragment NGWFs. For the benzene -ammonium system, re-initialisation to guess NGWFs at the polarisation stage was required in order to prevent under-convergence of the polarisation energy component.…”

Structural and fluctuational difference between two ends of Aβ amyloid fibril: MD simulations predict only one end has open conformations

“…According to Han and Schulten, the extension speed is 40 times faster at the even end than at the odd end because the additional A β peptide is locked in by the exposed hydrophobic residues at the even end38. However, Schwierz et al 39. reported a much smaller difference in the odd- and even-end extension speeds than that reported by Han and Schulten.…”

“…In previous MD studies of A β fibril extension3839, an A β peptide was added to either end of the fibril, while restraining the positions of the A β atoms at the end. According to Han and Schulten, the extension speed is 40 times faster at the even end than at the odd end because the additional A β peptide is locked in by the exposed hydrophobic residues at the even end38.…”

An Account of Amyloid Oligomers: Facts and Figures Obtained from Experiments and Simulations

“…We are not aware of simulations that have focused on the structures formed as a result of secondary nucleation (Figure ). However, we note that multiple simulation studies investigating the process of fibril elongation as a result of monomer addition to a preformed protofibril have been performed . The two‐step, dock‐and‐lock mechanism is currently the generally accepted mechanism for fibril elongation .…”