Principal Investigators

Photo of Dmitri Klimov, Ph.D.
Dmitri Klimov, Ph.D.
Associate Professor
George Mason University

Photo of Christopher Lockhart
Christopher Lockhart
Ph.D. Candidate
George Mason University


The current lack of understanding about the molecular origins of Alzheimer's Disease (AD) greatly limits our ability to rationally design AD therapies. Although the ultimate elucidation of these molecular mechanisms will require the combined efforts of neurologists, molecular biologists and others in the field of AD research, we are addressing the challenge with all-atom computational modeling of particular protein-cell interactions that are thought to be responsible for neuronal cell death in AD patients. Knowledge gained through these simulations about the nature of these interactions could provide important clues that will help researchers design effective AD treatments.

Interactions of Aβ peptides with cellular membranes

Small Aβ peptides have been identified as apparent agents of AD, causing death of neuron cells over the course of disease progression. Specifically, it is believed that, when Aβ peptides associate with each other and form aggregates, they become cytotoxic to cells.

However, it is not known why Aβ aggregates are cytotoxic. Is it because they interact with cellular membranes, disordering them and causing uncontrollable flow of ions, which in turn leads to cell death? Or does the same outcome result from Aβ aggregates forming structured channels in the membrane?

Animated Molecular Dynamics Simulation
Binding and initial penetration of Alzheimer’s peptide Aβ into cellular membrane simulated via computational modeling

In our recent study, published in the Journal of Physical Chemistry, we analyzed how individual Aβ peptides bind and penetrate a model lipid bilayer, which serves as a less complex and more computationally approachable proxy for a cellular membrane. We showed that upon binding the peptide undergoes dramatic structural transition, forming a helical structure, and we explained this observation based on Aβ sequence properties.

With the simulations being supported by the CAAD project, we are studying aggregation of Aβ peptides mediated by cellular membranes, with the goal of answering the questions posed above. These efforts are partially supported by NIH, specifically, the National Institute of Aging, through the grant awarded to George Mason University and Parabon Computation.

Implications for other disorders

Research into Aβ peptides, although most prominently focused on Alzheimer's disease, also has implications for other related syndromes, such as mild cognitive impairment. Furthermore, traumatic brain injury due to sports or other activities has also been linked to Aβ loads in affected brains. Therefore, understanding the cytotoxic mechanisms of Aβ will not only have a lasting impact on Alzheimer's research, but can help resolve related issues in other indications as well.