Justin Lemkul

Synopsis:

Dr. Lemkul investigates biomolecular structure-function relationships using computational
methods, focusing primarily on proteins and nucleic acids. The insights from this work are used
for novel drug design against a range of chronic diseases.

Description:

The Lemkul Lab applies atomistic molecular dynamics (MD) simulations to systems of biological interest, with an emphasis on proteins and nucleic acids related to disease. Driving these simulations is a cutting-edge polarizable force field, which the lab has previously shown to be critical in understanding the properties of amyloidogenic peptides and proteins, the structural dynamics and ion binding properties of nucleic acids, and of water molecules in close proximity to biomolecules and ions, as they behave differently from bulk water molecules.

The Lemkul Lab has three main focus areas: (1) understanding the driving forces for amyloidogenic peptide misfolding and aggregation, (2) elucidating the driving forces and conformational ensembles of DNA and RNA G-quadruplexes (GQs), and (3) using MD simulations as part of computer-aided drug design. Dozens of human diseases feature amyloid aggregation, including Alzheimer’s, Parkinson’s, and type 2 diabetes. Targeting amyloid aggregates with small molecules and antibodies has met with limited success; therefore, a greater understanding of the earliest events in the aggregation cascade, specifically monomer unfolding and conformational ensembles, is required. GQs are gene regulatory elements found in both DNA and RNA, formed by Hoogsteen base-pairing in guanine-rich sequences and stabilized by K+ ions. By targeting them with small molecules, gene expression can be selectively turned on or off as a function of GQ stability. This strategy opens new avenues for drug design in several types of cancer and neurodegenerative diseases; by targeting unique structures in DNA and RNA rather than proteins, it is expected that side effects will be minimized or possibly eliminated. Our ongoing simulations continue to provide new insights into the conformational preferences and stabilizing forces within DNA and RNA GQ. From the data generated in simulations, Dr. Lemkul's lab will pursue drug design strategies to address a wide range of human disorders.