Understanding the Earliest Stages of Amyloid Formation
Amyloid-related diseases are associated with the abnormal assembly of proteins into oligomers and fibrils. However, these proteins do not follow a single, uniform aggregation pathway. They can form multiple structurally distinct assemblies, each characterized by different interactions, levels of stability, and biological effects. A central focus of our research is the primary nucleation stage, during which individual protein molecules first associate to form dimers and small oligomers. These early assemblies are highly dynamic and structurally heterogeneous, making them challenging to observe experimentally. Nevertheless, they may play a major role in cellular toxicity and disease progression. We investigate the molecular mechanisms underlying the formation of amyloid-beta, alpha-synuclein, amylin, tau, and related peptide systems. By constructing and simulating different structural models, we identify the interactions that stabilize early aggregates and determine whether they develop into fibrillar structures, transient intermediates, or alternative off-pathway assemblies.
Biological Regulation of Protein Aggregation
The body contains proteins and peptides that can regulate amyloid formation. Some may inhibit aggregation, alter oligomer structure, trap aggregation-prone species, or prevent productive interactions between protein molecules. We investigate the molecular effects of endogenous regulators such as insulin, insulin-degrading enzyme, and naturally occurring neuropeptides. Rather than treating these molecules only as enzymes or binding partners, we examine how their structure and conformational dynamics influence amyloid assemblies. For example, a regulatory protein may separate two amyloid monomers, stabilize a nonproductive complex, or alter the orientation of an oligomer without directly degrading it. Understanding these non-proteolytic mechanisms may provide new perspectives on the natural regulation of amyloid aggregation.
Metals and the Molecular Environment
Protein self-assembly is strongly influenced by the surrounding chemical and biological environment. Metal ions, membranes, pH, post-translational modifications, and interactions with other biomolecules can reshape the conformational landscape of amyloidogenic proteins. Our research examines how zinc, copper, and other metal ions bind to specific residues and alter the structure, flexibility, stability, and aggregation pathways of proteins and peptides. We study how these effects depend on metal concentration, binding-site geometry, stoichiometry, and the initial conformation of the molecular assembly. We also investigate how the membrane environment influences oligomer organization and protein aggregation. These studies help explain why the same protein may behave differently under distinct physiological or pathological conditions.
Interactions Between Amyloidogenic Proteins
Neurodegenerative and metabolic diseases are often studied independently, although their associated proteins can coexist within the same biological environment. Growing evidence suggests that different amyloidogenic proteins may directly interact and influence one another's aggregation. We study cross-seeding and co-assembly between proteins such as amyloid-beta, alpha-synuclein, and amylin. These systems provide molecular models for understanding the possible connections between Alzheimer's disease, Parkinson's disease, dementia, and type 2 diabetes. Our simulations reveal how one protein can stabilize, disrupt, or redirect the assembly of another. This work contributes to a broader understanding of why amyloid-related diseases may share common molecular mechanisms and why mixed protein assemblies may behave differently from aggregates formed by a single protein.
Our Computational Approach
Our work combines all-atom molecular dynamics simulations with structural modeling, energetic analysis, conformational clustering, secondary-structure analysis, interaction-network analysis, and comparative studies of polymorphic molecular assemblies.
We use experimentally determined structures whenever available and develop biologically motivated models for systems that remain unresolved. Rather than relying on a single simulated structure, we analyze ensembles of conformations to capture the flexibility and heterogeneity of proteins and peptides.
Many of our projects are conducted in collaboration with experimental research groups. Computational predictions are compared with data obtained through spectroscopy, microscopy, biochemical measurements, peptide synthesis, and other structural and biophysical methods. This integration allows us to formulate molecular mechanisms that can be experimentally examined and refined.
