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

A Suite of Tutorials for the WESTPA Rare-Events Sampling Software [Article v1.0]

Bogetti AT, Mostofian B, Dickson A, Pratt AJ, Saglam AS, Harrison PO, Adelman JL, Dudek M, Torrillo PA, DeGrave AJ, Adhikari U, Zwier MC, Zuckerman DM, Chong LT. LiveCoMS. (2019)

The weighted ensemble (WE) strategy has been demonstrated to be highly efficient in generating pathways and rate constants for rare events such as protein folding and protein binding using atomistic molecular dynamics simulations. Here we present five tutorials instructing users in the best practices for preparing, carrying out, and analyzing WE simulations for various applications using the WESTPA software. Users are expected to already have significant experience with running standard molecular dynamics simulations using the underlying dynamics engine of interest (e.g. Amber, Gromacs, OpenMM). The tutorials range from a molecular association process in explicit solvent to...

REVO: Resampling of ensembles by variation optimization

Donyapour N., Roussey N.M. and Dickson A.*. J. Chem. Phys.. (2019)

Conventional molecular dynamics simulations are incapable of sampling many important interactions in biomolecular systems due to their high dimensionality and rough energy landscapes. To observe rare events and calculate transition rates in these systems, enhanced sampling is a necessity. In particular, the study of ligand-protein interactions necessitates a diverse ensemble of protein conformations and transition states, and for many systems, this occurs on prohibitively long time scales. Previous strategies such as WExplore that can be used to determine these types of ensembles are hindered by problems related to the regioning of conformational space. Here, we propose...

Markov-State Transition Path Analysis of Electrostatic Channeling

Liu Y, Hickey DP, Minteer SD, Dickson A*, Barton SC*. J. Phys. Chem. C. (2019)

Electrostatic channeling is a naturally-occurring approach to control the flux of charged intermediates in catalytic cascades. Computational techniques have enabled quantitative understanding of such mechanisms, augmenting experimental approaches by modeling molecular interactions in atomic detail. In this work, we report the first utilization of a Markov State Model (MSM) to describe the surface diffusion of a reaction intermediate, glucose 6-phosphate, on an artificially modified cascade where hexokinase and glucose-6-phosphate dehydrogenase are covalently conjugated by a cationic oligopeptide bridge. Conformation space networks are used to represent intermediate transport on enzyme surfaces, along with committor probabilities that assess...

Selectivity, ligand deconstruction, and cellular activity analysis of a BPTF bromodomain inhibitor

Kirberger SE, Ycas PD, Johnson JA, Chen C, Ciccone M, Lu RWW, Urick AK, Zahid H, Shi K, Aihara H, McAllister S, Kashani-Sabet M, Shi J, Dickson A, dos Santos CO* and Pomerantz W*. Org. Biomol. Chem.. (2019)

Bromodomain and PHD finger containing protein transcription factor (BPTF) is an epigenetic protein involved in chromatin remodelling and is a potential anticancer target. The BPTF bromodomain has one reported small molecule inhibitor (AU1, rac-1). Here, advances made on the study of rac-1 are reported, specifically, identification of the active enantiomer for binding to the bromodomain, and reduction in off-target binding to known kinase targets. Additionally, a ligand deconstruction analysis was conducted to characterize important pharmacophores for engaging the BPTF bromodomain. These studies have been enabled by a protein-based fluorine NMR approach, highlighting the versatility of the...

Mapping the Ligand Binding Landscape

Dickson A*. Biophysical Journal. (2018)

The interaction between a ligand and a protein involves a multitude of conformational states. To achieve a particular deeply-bound pose the ligand must search across a rough free energy landscape, with many metastable minima. Creating maps of the ligand binding landscape is a great challenge, as binding and release events typically occur on timescales that are beyond the reach of molecular simulation. The WExplore enhanced sampling method is well-suited to build these maps, as it is designed to broadly explore free-energy landscapes, and is capable of simulating ligand release pathways that occur on timescales as long...

Predicting ligand binding affinity using on- and off-rates for the SAMPL6 SAMPLing challenge

Dixon T, Lotz SD and Dickson A*. Journal of Computer-Aided Molecular Design. (2018)

Interest in ligand binding kinetics has been growing rapidly, as it is being discovered in more and more systems that ligand residence time is the crucial factor governing drug efficacy. Many enhanced sampling methods have been developed with the goal of predicting ligand binding rates (kon) and/or ligand unbinding rates (koff) through explicit simulation of ligand binding pathways, and these methods work by very different mechanisms. Although there is not yet a blind challenge for ligand binding kinetics, here we take advantage of experimental measurements and rigorously computed benchmarks to compare estimates of KD calculated as...

Structural Insights into Lethal Contractural Syndrome Type 3 (LCCS3) Caused by a Missense Mutation of PIP5Ky

Xuaunkun Zeng, Arzu Uyar, Dexin Sui, Nazanin Donyapour, Dianqing Wu, Alex Dickson, Jian Hu. Biochemical Journal. (2018)

Signaling molecule phosphatidylinositol 4,5-bisphosphate (PIP2) is produced primarily by phosphatidylinositol 4-phosphate 5-kinase (PIP5K). PIP5K is essential for the development of the human neuronal system, which has been exemplified by a recessive genetic disorder, lethal congenital contractural syndrome type 3 (LCCS3), caused by a single aspartate-to-asparagine mutation in the kinase domain of PIP5Ky. So far, the exact role of this aspartate residue has yet to be elucidated. In this work, we conducted structural, functional and computational studies on a zebrafish PIP5Ka variant with a mutation at the same site. Compared with the structure of the wild type...

A biosensor-based framework to measure latent proteostasis capacity

Wood RJ, Ormsby AR, Radwan M, Cox D, Sharma A, Vopel T, Ebbinghaus S, Oliveberg M, Reid GE, Dickson A & Hatters DM*. Nature Communications. (2018)

The pool of quality control proteins (QC) that maintains protein-folding homeostasis (proteostasis) is dynamic but can become depleted in human disease. A challenge has been in quantitatively defining the depth of the QC pool. With a new biosensor, flow cytometry-based methods and mathematical modeling we measure the QC capacity to act as holdases and suppress biosensor aggregation. The biosensor system comprises a series of barnase kernels with differing folding stability that engage primarily with HSP70 and HSP90 family proteins. Conditions of proteostasis stimulation and stress alter QC holdase activity and aggregation rates. The method reveals the...

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

Lotz SD and Dickson A*. Journal of the American Chemical Society. (2018)

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*. Journal of Chemical Theory and Computation. (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...