Side Chain Geometry Determines the Fibrillation Propensity of a Minimal Two-Beads-per-Residue Peptide Model

Abstract

The molecular mechanism of fibrillation is an important issue for understanding peptide aggregation. In our previous work, we demonstrated that the interchain attraction and intrachain bending stiffness control the aggregation kinetics and transient aggregate morphologies of a one-bead-per-residue implicit solvent peptide model. However, that model did not lead to fibrillation. In this work, we study the molecular origin of fibril formation using a two-beads-per-residue model, where one bead represents the backbone residue atoms and the other the side chain atoms. We show that the side chain geometry determines the fibrillation propensity that is further modulated by the modified terminal beads. This allows us to bring out the effects of side chain geometry and terminal capping on the fibrillation propensity. Our model does not assume a secondary structure and is, perhaps, the simplest bead-based chain model leading to fibrillation.

Modified Smoluchowski Rate Equations for Aggregation and Fragmentation in Finite Systems

“…First, we discuss three stochastic models for aggregation in finite systems, N = 5 and N = 20, and show that the modified Smoluchowski equations can provide a good approximation for the average concentrations even for small systems, N = 20. Second, we consider the aggregation kinetics of a coarse-grained molecular dynamics model that reproduces the various morphologies of peptide aggregates . We show how our approach can be used to develop a kinetic model that describes the initial aggregation–fragmentation kinetics.…”

“…Now we demostrate how the modified Smoluchowski equations () can be used to infer the kinetic model from molecular dynamics simulations of a small system. We consider a coarse-grained two-beads-per-residue model that reproduces diverse morphologies of the aggregates . In this homopeptide model each residue is represented by two beads: one for the backbone and one for the side chain.…”

“…The termini beads interact via the LJ potentials with interaction strengths corresponding to the repulsion and attraction between the like or oppositely charged ends, respectively. A detailed model description is available in our previous paper …”

“…Second, we consider the aggregation kinetics of a coarse-grained molecular dynamics model that reproduces the various morphologies of peptide aggregates. 30 We show how our approach can be used to develop a kinetic model that describes the initial aggregation–fragmentation kinetics. Third, we consider the aggregation kinetics of a coarse-grained model of a short polyglutamine peptide (Q12).…”

“…A detailed model description is available in our previous paper. 30 We used the GROMACS 2020.5 package 31 for the simulation and MDAnalysis 32 together with python homemade scripts for data analysis. The periodic boundary conditions were used in all dimensions.…”