UC Santa Barbara

Protein aggregation involves self-assembly of normally soluble proteins or peptides into supramolecular structures. This process is particularly important due to its involvement in several amyloid diseases, such as Parkinson's, Alzheimer's, and Type II diabetes. Several fibrillization mechanisms have been proposed, including a condensation-ordering mechanism where ordered fibril structures emerge from disordered oligomers and a dock-lock mechanism where a growing fibril induces attached polypeptides to organize individually into fibril-compatible conformations.

We present a series of computational studies using a coarse-grained peptide aggregate model that exhibits a rich diversity of structures: amorphous/disordered aggregates, beta-barrels, multi-layered fibrils, and aggregates of mixed type. Our model has a tunable backbone stiffness that governs the propensity to form fibrils in bulk solution. In this work, we investigate how this beta-sheet propensity couples with the properties of a surface template to influence the mechanism of aggregation. Here, we focus on peptide aggregation in the presence of three templates: a solid surface, the surface of a pre-existing aggregate seed, and a lipid bilayer.

Aggregation on solid hydrophilic or hydrophobic surfaces frequently occurs in many experimental setups. We find that the solid surface strongly biases toward the formation of fibrillar aggregates. Peptide-peptide interactions and surface attraction couple cooperatively on a solid surface to influence the binding/aggregation transition. Aggregation and binding occur almost simultaneously since the surface's crystal symmetry enforces a preferred direction of bound fibril growth, thus accelerating the process.

Seeding peptides with compatible aggregates removes the nucleation barrier for aggregation. We find that the aggregation mechanism is strongly dependent on the beta-sheet propensity of both the seed and bulk peptides. Additionally, bulk peptides that exhibit polymorphism can have multiple pathways to aggregation depending on which class of aggregate they initially form. We find that a fibrillar seed can induce amorphous-prone peptides into fibrillar structures via a condensation-ordering mechanism, thus sequestering potentially cytotoxic oligomers into a more inert form.

We simulate aggregation on lipid bilayers in an effort to approximate the complexity of the cellular milieu. While aggregation in vivo would occur in the presence of membrane surfaces, few simulation studies have been conducted on this combined system due to its computational complexity.

We have determined that a membrane surface, like a crystal surface, biases toward fibrillar aggregates. However, membrane undulations disturb multi-layered fibrils into non-planar beta-sheet structures, such as beta-barrels. The presence of fibrils on the membrane also affects its fluid properties, creating a hexagonally packed lipid ordering underneath the fibrils, locally increasing its bending modulus and aligning lipid tilt to the orientation of the peptides. Thus peptide aggregation and membrane fluidity affect each other's structure and dynamics.

The key general features of a surface that control its modulation of peptide aggregation are its structural order and fluidity. An ordered, rigid template biases more strongly toward fibrillar structures and restricts the set of aggregation pathways and morphologies. The dynamic nature of a fluid surface biases less toward fibrils and enhances the range of aggregation dynamics.