We present a Water Explicit Polarizable PROtein coarse-grained Model (WEPPROM) that can be used to characterize the driving forces behind peptide folding and/or peptide aggregation in solution and at lipid bilayer interfaces. Each amino acid is coarse-grained with two beads, a backbone, and a side chain. Although the backbone beads are modeled as polar entities, side chains are hydrophobic, polar, or charged, thus allowing the exploration of how sequence patterning determines peptide fold. The change of orientation of the atoms of the coarse-grained unit is captured by the addition of two oppositely charged dummy particles inside the backbone coarse-grained bead. These two dummy charges represent a dipole that can fluctuate, thus introducing structural polarization into the coarse-grained model. Realistic alpha/beta content is achieved de novo without any biases in the force field toward a particular secondary structure. In line with this model, a coarse-grained model for anionic and zwitterionic lipids that account for dipolar intricacies of the head group region will be described as well. The application of this model to study the aggregation of amyloid beta 16-22 (KLVFFAE) peptides on lipid membranes will be discussed. In particular, the effect of membrane curvature and lipid headgroup charge: zwitterionic (phosphatidylcholine-PC) or anionic (phosphatidylserine-PS) on amyloid-beta will be shown. Our analyses present an extensive overview of multiple pathways for peptide absorption and biomechanical forces governing peptide folding and aggregation. In agreement with experimental observations, anionic PS molecules promote extended configurations in Aβ peptides that contribute towards faster emergence of ordered β-sheet-rich peptide assemblies compared to PC, suggesting faster fibrillation. Moreover, an increase in membrane curvature also leads to faster and more ordered aggregation. In addition, lower cumulative rates of peptide aggregation in PS due to higher peptide–lipid interactions and slower lipid diffusion result in multiple distinct ordered peptide aggregates that can serve as nucleation seeds for subsequent Aβ aggregation.

Water-explicit polarizable coarse-grained models of peptide-lipid systems

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.