* = corresponding author

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...

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...

Multiscale Modeling of a Conditionally Disordered pH-Sensing Chaperone

Ahlstrom LS, Law SM, Dickson A and Brooks III CL*. J. Mol. Biol. (2015)

The pH-sensing chaperone HdeA promotes the survival of enteropathogenic bacteria during transit through the harshly acidic environment of the mammalian stomach. At low pH, HdeA transitions from an inactive, folded, dimer to chaperone-active, disordered, monomers to protect against the acidiinduced aggregation of periplasmic proteins. Toward achieving a detailed mechanistic understanding of the pH response of HdeA, we develop a multiscale modeling approach to capture its pH-dependent thermodynamics. Our approach combines pKa (logarithmic acid dissociation constant) calculations from all-atom constant pH molecular dynamics simulations with coarse-grained modeling and yields new, atomic-level, insights into HdeA chaperone function that...

pH-Dependent Transient Conformational States Control Optical Properties in Cyan Fluorescent Protein

Laricheva EN, Goh GB, Dickson A and Brooks III CL*. J. Am. Chem. Soc. (2015)

A recently engineered mutant of cyan fluorescent protein (WasCFP) that exhibits pH-dependent absorption suggests that its tryptophan-based chromophore switches between neutral (protonated) and charged (deprotonated) states depending on external pH. At pH 8.1, the latter gives rise to green fluorescence as opposed to the cyan color of emission that is characteristic for the neutral form at low pH. Given the high energy cost of deprotonating the tryptophan at the indole nitrogen, this behavior is puzzling, even if the stabilizing effect of the V61K mutation in proximity to the protonation/deprotonation site is considered. Because of its potential...

Efficient in silico exploration of RNA interhelical conformations using Euler angles and WExplore

Dickson A, Mustoe AM, Salmon LS and Brooks III CL*. Nucl. Acids Res. (2014)

HIV-1 TAR RNA is a two-helix bulge motif that plays a critical role in HIV viral replication and is an important drug target. However, efforts at designing TAR inhibitors have been challenged by its high degree of structural flexibility, which includes slow large-amplitude reorientations of its helices with respect to one another. Here, we use the recently introduced algorithm WExplore in combination with Euler angles to achieve unprecedented sampling of the TAR conformational ensemble. Our ensemble achieves similar agreement with experimental NMR data when compared with previous TAR computational studies, and is generated at a fraction...

WExplore: Hierarchical Exploration of High-Dimensional Spaces Using the Weighted Ensemble Algorithm

Dickson A and Brooks III CL*. J. Phys. Chem. B (2014)

As most relevant motions in biomolecular systems are inaccessible to conventional molecular dynamics simulations, algorithms that enhance sampling of rare events are indispensable. Increasing interest in intrinsically disordered systems and the desire to target ensembles of protein conformations (rather than single structures) in drug development motivate the need for enhanced sampling algorithms that are not limited to two-basin problems, and can efficiently determine structural ensembles. For systems that are not well-studied, this must often be done with little or no information about the dynamics of interest. Here we present a novel strategy to determine structural ensembles...

Quantifying Chaperone-Mediated Transitions in the Proteostasis Network of E. coli

Dickson A and Brooks III CL*. PLOS Comp. Biol. (2013)

For cells to function, the concentrations of all proteins in the cell must be maintained at the proper levels (proteostasis). This task - complicated by cellular stresses, protein misfolding, aggregation, and degradation - is performed by a collection of chaperones that alter the configurational landscape of a given client protein through the formation of protein-chaperone complexes. The set of all such complexes and the transitions between them form the proteostasis network. Recently, a computational model was introduced (FoldEco) that synthesizes experimental data into a system-wide description of the proteostasis network of E. coli. This model describes...

Binding and Folding of the Small Bacterial Chaperone HdeA

Ahlstrom LS, Dickson A and Brooks III CL*. J. Phys. Chem. B (2013)

The small pH stress-sensing chaperone HdeA helps pathogenic enteric E. coli survive passage through the severely acidic environment of the mammalian stomach. Under stress conditions, HdeA transitions from an inactive folded dimer to a chaperone-active unfolded monomer to prevent the acid-induced aggregation of periplasmic proteins. Here we use a topology-based Go-like model to delineate the relationship between dimer interface formation and monomer folding and to better understand the structural details of the chaperone activation mechanism. Free energy surfaces show that dimer interface formation and monomer folding proceed concurrently through an on-pathway dimeric intermediate in which one...

Native States of Fast-Folding Proteins Are Kinetic Traps

Dickson A and Brooks III CL*. J. Am. Chem. Soc. (2013)

It has been suggested that the native state of a protein acts as a kinetic hub that can facilitate transitions between nonnative states. Using recently developed tools to quantify mediation probabilities (hub scores), we quantify hub-like behavior in atomic resolution trajectories for the first time. We use a data set of trajectory ensembles for 12 fast-folding proteins previously published by D. E. Shaw Research (Lindorff-Larsen, K.; et al. How Fast-Folding Proteins Fold. Science 2011, 334, 517) with an aggregate simulation time of over 8.2 ms. We visualize the free-energy landscape of each molecule using configuration space...

Quantifying Hub-like Behavior in Protein Folding Networks

Dickson A and Brooks III CL*. J. Chem. Theory Comput. (2012)

The free energy landscape of a protein is a function of many interdependent degrees of freedom. For this reason, conceptual constructs (e.g., funnels) have been useful to visualize these landscapes. One relatively new construct is the idea of a hub-like native state that is the final destination of many noninterconverting folding pathways. This is in contrast to the idea of a single predominant folding pathway connecting the native state to a rapidly interconverting ensemble of unfolded states. The key quantity to distinguish between these two ideas is the connectivity of the unfolded ensemble. We present a...

Entrainment of a driven oscillator as a dynamical phase transition

Dickson A, Tabei SMA and Dinner AR. Phys. Rev. E (2011)

Large deviation theory has emerged as the natural language with which to study transitions between dynamical phases, such as the glass transition. Here we use this approach to show that the entrainment of an oscillator to an external driving force can be described as a phase transition between two regions in a joint space-time representation. Specifically, we numerically obtain exact solutions of the large deviation function for a discrete, finite model of an oscillator under a periodically varying external force. We find that the first derivative of the expectation value of the current diverges in the...