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

Kinetics of Ligand Binding Through Advanced Computational Approaches: A Review

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

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...

Ligand Release Pathways Obtained with WExplore: Residence Times and Mechanisms

Dickson A* and Lotz SD. J. Phys. Chem. B.. (2016)

The binding of ligands with their molecular receptors is of tremendous importance in biology. Although much emphasis has been placed on characterizing binding sites and bound poses that determine the binding thermodynamics, the pathway by which a ligand binds importantly determines the binding kinetics. The computational study of entire unbiased ligand binding and release pathways is still an emerging field, made possible only recently by advances in computational hardware and sampling methodologies. We have developed one such method (WExplore) that is based on a weighted ensemble of trajectories, which we apply to ligand release for the...

Coupled folding and binding with 2D Window-Exchange Umbrella Sampling

Dickson A, Ahlstrom LS and Brooks III CL*. J. Comp. Chem.. (2015)

Intrinsically disordered regions of proteins can gain structure by binding to a partner. This process, of coupled folding and binding (CFaB), is a fundamental part of many important biological processes. Structure-based models have proven themselves capable of revealing fundamental aspects of how CFaB occurs, however, typical methods to enhance the sampling of these transitions, such as replica exchange, do not adequately sample the transition state region of this extremely rare process. Here, we use a variant of Umbrella Sampling to enforce sampling of the transition states of CFaB of HdeA monomers at neutral pH, an extremely...