Research Overview

At the atomic level, the molecules in our bodies are in constant motion, and undergoing constant change. The motions are incredibly rich; they range from the isomerization of side-chains, to the formation and destruction of large intermolecular complexes, to the birth and death of the molecules themselves. A deep understanding of these motions can radically improve our understanding of health and disease through rational design, where drugs target specific receptors chosen for a specific molecular impact.

The Dickson laboratory uses computational techniques such as molecular dynamics to simulate the motions of biomolecules (protein, RNA and DNA). These numerical experiments extend our knowledge beyond the "snapshots" provided by X-ray crystallography and NMR, and provide the entire landscape of conformations accessible to a molecular system. Our goal is to use simulations to gain a deep understanding of the ligand binding process, and use this knowledge to aid ongoing drug discovery efforts.

We also use larger-scale network models of biological processes to gain understanding for processes that involve many different molecular species, such as chaperone action in the cell. This allows a much broader reach, and can synthesize findings from simulation and experiment into a coherent biological model. Working in both worlds simultaneously allows for a multiscale disease-targeting strategy that is detailed enough to capture atomic-level perturbations, and broad enough to capture the cell-level consequences of disease.

Recent Publications

Unbiased Molecular Dynamics of 11 min Timescale Drug Unbinding Reveals Transition State Stabilizing Interactions

Lotz SD and Dickson A*. In Revision. (2017)

Ligand (un)binding kinetics is being recognized as a determinant of drug specificity and efficacy in an increasing number of systems. However, the calculation of kinetics and the simulation of drug unbinding is more difficult than computing thermodynamic quantities, such as binding free energies. Here we present the first full simulations of an unbinding process at pharmacologically relevant timescales (11 min), without the use of biasing forces, detailed prior knowledge, or specialized processors using the weighted ensemble based algorithm, WExplore. These simulations show the inhibitor TPPU unbinding from its enzyme target soluble epoxide hydrolase (sEH), which is...

Long-Range Changes in Neurolysin Dynamics Upon Inhibitor Binding

Uyar A and Dickson A*. In Revision. (2017)

Crystal structures of neurolysin, which is a zinc metallopeptidase (neuropeptidase), do not show significant conformational changes upon the binding of an allosteric inhibitor. Neurolysin has a prolate ellipsoid shape with a deep channel that runs almost the entire length of the molecule. In this deep channel, neurolysin hydrolyzes the short neuropeptide neurotensin to create inactive shorter fragments and thus controls the neurotensin level in the tissue. The protein is of interest as a therapeutic target since changes in neurotensin level have been implicated in cardiovascular and neurological disorders and cancer, and inhibitors of neurolysin activity have...

Kinetics of Ligand Binding Through Advanced Computational Approaches: A Review

Dickson A*, Tiwary P and Vashisth H. Current Topics in Medicinal Chemistry. (2017)

Ligand residence times and binding rates have been found to be useful quantities to consider during drug design. The underlying structural and dynamic determinants of these kinetic quantities are difficult to discern. Driven by developments in computational hardware and simulation methodologies, molecular dynamics (MD) studies of full binding and unbinding pathways have emerged recently, showing these structural and dynamic determinants in atomic detail. However, the long timescales related to drug binding and release are still prohibitive to conventional MD simulation. Here we discuss a suite of enhanced sampling methods that have been applied to the study...

Multiple Unbinding Pathways and Ligand-Induced Destabilization Revealed by WExplore

Dickson A* and Lotz SD. Biophysical Journal. (2017)

We report simulations of full ligand exit pathways for the trypsin-benzamidine system, generated using the sampling technique WExplore. WExplore is able to observe millisecond-scale unbinding events using many nanosecond-scale trajectories that are run without introducing biasing forces. The algorithm generates rare events by dividing the coordinate space into regions, on-the-fly, and balancing computational effort between regions through cloning and merging steps, as in the weighted ensemble method. The averaged exit flux yields a ligand exit rate of 180 microseconds, which is within an order of magnitude of the experimental value. We obtain broad sampling of ligand...

Optimal Allosteric Stabilization Sites Using Contact Stabilization Analysis

Dickson A*, Bailey CT and Karanicolas J. Journal of Computational Chemistry. (2016)

Proteins can be destabilized by a number of environmental factors such as temperature, pH and mutation. The ability to restore function by small molecule stabilizers, or the introduction of disulde bonds, would be a very powerful tool, but the physical principles that drive this stabilization are not well understood. The first problem lies is in choosing an appropriate binding site or disulfide bond location that will best confer stability to the active site and restore function. Here we present a general framework for predicting which allosteric binding sites correlate with stability in the active site. Using...

Capturing a Dynamic Chaperone-Substrate Interaction Using NMR-Informed Molecular Modeling

Salmon L, Ahlstrom LS, Horowitz S, Dickson A, Brooks III CL* and Bardwell JCA*. J. Am. Chem. Soc.. (2016)

Chaperones maintain a healthy proteome by preventing aggregation and by aiding in protein folding. Precisely how chaperones influence the conformational properties of their substrates, however, remains unclear. To achieve a detailed description of dynamic chaperone-substrate interactions, we fused site-specific NMR information with coarse-grained simulations. Our model system is the binding and folding of a chaperone substrate, immunity protein 7 (Im7), with the chaperone Spy. We first used an automated procedure in which NMR chemical shifts inform the construction of system-specific force fields that describe each partner individually. The models of the two binding partners are then...