Hydrodynamic effects on β-amyloid (16-22) peptide aggregation

Abstract

Computer simulations based on simplified representations are routinely used to explore the early steps of amyloid aggregation. However, when protein models with implicit solvent are employed, these simulations miss the effect of solvent induced correlations on the aggregation kinetics and lifetimes of metastable states. In this work, we apply the multi-scale Lattice Boltzmann Molecular Dynamics technique (LBMD) to investigate the initial aggregation phases of the amyloid Aβ16-22 peptide. LBMD includes naturally hydrodynamic interactions (HIs) via a kinetic on-lattice representation of the fluid kinetics. The peptides are represented by the flexible OPEP coarse-grained force field. First, we have tuned the essential parameters that control the coupling between the molecular and fluid evolutions in order to reproduce the experimental diffusivity of elementary species. The method is then deployed to investigate the effect of HIs on the aggregation of 100 and 1000 Aβ16-22 peptides. We show that HIs clearly impact the aggregation process and the fluctuations of the oligomer sizes by favouring the fusion and exchange dynamics of oligomers between aggregates. HIs also guide the growth of the leading largest cluster. For the 100 Aβ16-22 peptide system, the simulation of ∼300 ns allowed us to observe the transition from ellipsoidal assemblies to an elongated and slightly twisted aggregate involving almost the totality of the peptides. For the 1000 Aβ16-22 peptides, a system of unprecedented size at quasi-atomistic resolution, we were able to explore a branched disordered fibril-like structure that has never been described by other computer simulations, but has been observed experimentally.

Multiscale simulation of molecular processes in cellular environments

“…Lateral branching is described theoretically by a second nucleation mechanism [46], but while observed experimentally for some proteins [47,48], it has never been reported from molecular simulations. In a recent work [49] reporting on the effect of hydrodynamics on the aggregation process of Aβ 16−22 peptides in systems of different sizes, we have demonstrated that hydrodynamic interactions not only speed up the aggregation with respect to standard Langevin dynamics, but also enhance the fluctuations of the sizes of the formed clusters along the aggregation. It was speculated that the peptides aggregates act on the solution as active particles [9], and the change of their conformations and sizes generate coherent fluid flows that further favour the fusion of small entities in larger complexes.…”

Recent Advances in Coarse-Grained Models for Biomolecules and Their Applications

“…In a study for the Aβ16−22 peptide, it was defined by a flexible OPEP model and the initial aggregation phase study was done using multi-scale Lattice Boltzmann molecular dynamics. The hydrodynamic interaction effect was studied and found to enhance the aggregation process [106]. In another work, the OPEP model has been implied to study the amyloid fibril formation along with interactive simulations for peptide folding and response to mechanical stress caused by the surrounding fluid by catch bond proteins [105].…”

“…It is based upon the kinetic description of the solvent explained by the fluid dynamics under varied conditions. LB-based hydrodynamics in combination with the OPEP coarse-grained model for proteins have been reported to study the protein relaxation and aggregation processes [106,159,160].…”

Mesoscopic simulations at the physics-chemistry-biology interface

“…Amyoid aggregation represents an examplar instance of hydrodynamic forces impacting the formation of molecular aggregates. By studying a system of unprecedented size, LBPD simulations were able to explore a branched disordered fibril-like structure that had never been described by computer simulations before [97]. The results show that hydrodynamics forces also steer the growth of the leading largest cluster and impact the aggregation kinetics and the fluctuations of the oligomer sizes, by favouring the fusion and exchange dynamics of oligomers between aggregates.…”