Assistant Professor, Department of Biochemistry
Program Focus
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.
Current Projects
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.
Selected Publications
J.A. Lemkul and A.D. MacKerell, Jr. (2017) “Polarizable Force Field for DNA Based on the Classical Drude Oscillator: I. Refinement Using Quantum Mechanical Base Stacking and Conformational Energetics.” J. Chem. Theory Comput. 13 (5): 2053-2071. (PMC5484419)
J.A. Lemkul and A.D. MacKerell, Jr. (2017) “Polarizable Force Field for DNA Based on the Classical Drude Oscillator: II. Microsecond Molecular Dynamics Simulations of Duplex DNA.” J. Chem. Theory Comput. 13 (5): 2072-2085. (PMC5485260)
J.A. Lemkul and A.D. MacKerell, Jr. (2016) “Balancing Interactions of Mg2+ in Aqueous Solution and with Nucleic Acid Moieties For a Polarizable Force Field Based on the Classical Drude Oscillator Model.” J. Phys. Chem. B 120 (44): 11436-11448. (PMC5148688)
J.A. Lemkul, S.K. Lakkaraju, and A.D. MacKerell, Jr. (2016) “Characterization of Mg2+ Distributions around RNA in Solution.” ACS Omega 1 (4): 680-688. (PMC5088455)
J.A. Lemkul, J. Huang, B. Roux, and A.D. MacKerell, Jr. (2016) “An Empirical Polarizable Force Field Based on the Classical Drude Oscillator Model: Development History and Recent Applications.” Chem. Rev. 116 (9): 4983-5013. (PMC4865892)
S.K. Lakkaraju, J.A. Lemkul, J. Huang, and A.D. MacKerell, Jr. (2016) “DIRECT-ID: An Automated Method to Identify and Quantify Conformational Variations - Application to b2-adrenergic GPCR.” J. Comput. Chem. 37 (4): 416-425. (PMC4756637)
J.A. Lemkul, J. Huang, and A.D. MacKerell, Jr. (2015) “Induced Dipole-Dipole Interactions Influence Unfolding Pathways of Wild-Type and Mutant Amyloid b-Peptides.” J. Phys Chem. B 119 (51): 15574-15582. (PMC4690896)
J.A. Lemkul, B. Roux, D. van der Spoel, and A.D. MacKerell, Jr. (2015) “Implementation of Extended Lagrangian Dynamics in GROMACS for Polarizable Simulations Using the Classical Drude Oscillator Model.” J. Comput. Chem. 36 (19): 1473-1479. (PMC4481176)
J.A. Lemkul, A. Savelyev, and A.D. MacKerell, Jr. (2014) “Induced Polarization Influences the Fundamental Forces in DNA Base Flipping.” J. Phys. Chem. Lett. 5 (12): 2077-2083. (PMC4064933)