- Graduate Program Director
- Research area(s): Computational modeling of amyloidogenic proteins and G-quadruplexes, computer-aided drug design
Ph.D., Biochemistry, Virginia Tech, 2012
B.S. In Honors, Biochemistry Virginia Tech, 2007
- August 2017-present, Assistant Professor, Biochemistry, Virginia Tech
- July 2013-July 2017, Postdoctoral Fellow, Pharmaceutical Sciences and Computer-Aided Drug Design Center, University of Maryland, Baltimore
- May 2012-May 2013, Research Scientist, Biochemistry, Virginia Tech
Instructor, BCHM 4554 Biochemistry for Biophysics, 2021 – present
Instructor, BCHM 4784/5784 Advanced Applications in the Molecular Life Sciences, 2018 – 2019
Research in my group employs state-of-the-art molecular dynamics (MD) simulation models and methods to answer biochemical and biophysical questions and drive forward computer-aided drug design (CADD). By applying a theoretical approach to emerging problems in biology, we can gain insight into fundamental processes and disease states with unprecedented temporal and spatial resolution. Driving these investigations is the recently developed polarizable force field based on the classical Drude oscillator model.
1. G-Quadruplexes as Drug Targets
Guanine-rich sequences in DNA and RNA fold into G-quadruplex (GQ) structures of stacked guanine platforms to carry out important regulatory functions in cells. A number of human diseases, including many types of cancer, amyotrophic lateral sclerosis (Lou Gehrig's disease), and fragile X syndrome have been linked to aberrant GQ folding or interactions with cognate binding proteins. As such, GQ are potential therapeutic targets across a wide range of human disorders. Current MD force fields are generally unable to model GQ accurately due to inadequacies in ion interactions and properties of the DNA or RNA backbone. We are applying the cutting-edge Drude polarizable model to simulations of GQ to understand their conformational ensembles, folding pathways, and how to exploit them for novel drug design.
2. Protein Folding Disorders and Amyloid Peptides
Protein misfolding/unfolding and aggregation is linked to dozens of diseases, notably Alzheimer's, Parkinson's, and Type 2 diabetes. The proteins responsible for these pathological states have considerable sequence heterogeneity, and in fact nearly any protein can be induced to form an amyloid aggregate. The driving forces for these phenomena are poorly understood and difficult to interrogate experimentally. We have found that the use of explicit polarization in the simulation can elucidate specific side chain-backbone dipole-dipole interactions that contribute to α-helical instability in the Aβ peptide that is linked to Alzheimer's disease. Ongoing work in this area includes investigations of a number of amyloidogenic sequences and other model peptides to determine the driving forces for unfolding and the earliest events in amyloid disease states, during which therapeutic intervention will be most successful.
3. Properties of Small Molecules
The cellular environment is a complex milieu of microenvironments, ranging from the polar (aqueous) cytosol to less polar environments like protein binding sites and the interior of cellular membranes. As such, the diffusion, binding, and partitioning of small molecules like substrates, metabolites, and xenobiotics will be affected by the local electric fields in these microenvironments. To understand binding and partitioning thermodynamics, which are essential in drug design, a thorough examination of the effects of polarization is warranted. We are carrying out simulations of small molecules in biologically relevant environments to solve two principal aims: (1) to understand the impact of polarization and (2) to drive force field development and refinement towards a general polarizable force field for small molecules.
- D.S. Davidson, J.A. Kraus, J.M. Montgomery, and J.A. Lemkul* (2022) “Effects of Familial Alzheimer’s Disease Mutations on the Folding Free Energy and Dipole-Dipole Interactions of the Amyloid b-Peptide” J. Phys. Chem. B In 126 (39): 7552-7566. (NIHMS1838492)
- M.D. Polêto and J.A. Lemkul* (2022) “TUPÃ: Electric field analyses for molecular simulations” J. Comput. Chem. 43 (16): 1113-1119. (PMC9098685)
- A.M. Salsbury and J.A. Lemkul* (2021) “Monovalent Cation Recruitment and Competition around the c-kit1 G-Quadruplex Using Polarizable Simulations.” Biophys. J. 120 (11): 2249-2261. (PMC8390831)
- A.M. Salsbury, T.J. Dean, and J.A. Lemkul* (2020) “Polarizable Molecular Dynamics Simulations of Two c-kit Promoter G-Quadruplexes: Effect of Primary and Secondary Structure on Loop and Ion Sampling.” J. Chem. Theory Comput. 16 (5): 3430-3444. (PMC7221321)
- D.S. Davidson, A.M. Brown, and J.A. Lemkul* (2018) “Insights into Stabilizing Forces in Amyloid Fibrils of Differing Sizes from Polarizable Molecular Dynamics Simulations.” J. Mol. Biol. 430 (20): 3819-3834. (F1000 Prime Recommended paper)
Department of Biochemistry Outstanding Research Award, 2022
OpenEye Outstanding Junior Faculty Award, 2022
Department of Biochemistry Outstanding Teaching Award, 2021
Wiley Computers in Chemistry Outstanding Postdoc Award, 2016
Virginia Tech Graduate School Outstanding STEM Dissertation, 2013
College of Agriculture & Life Sciences Outstanding Doctoral Student, 2012
Kendall W. King Memorial Scholarship, 2011
Bruce M. Anderson Award, 2008
NSF MILES-IGERT Training Grant, 2008
Institute for Critical and Applied Technology Doctoral Fellowship, 2007