Michael Hagan

Brandeis University, Biophysics, Faculty Member

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Papers by Michael Hagan

Orientational order of motile defects in active nematics

by Gabriel S Redner, Stephen Decamp, and Michael Hagan

The study of equilibrium liquid crystals has lead to deep insights into the nature of ordered mat... more The study of equilibrium liquid crystals has lead to deep insights into the nature of ordered materials, as well as great technological advances in displays and other electro-optical devices. In comparison, little is known about active liquid crystals, which are driven away from equilibrium by the autonomous motion of their constituent particles. By identifying and tracking large ensembles of topological defects in experimental and computational realizations of active nematics, we discover a phase in which transient motile defects spontaneously break rotational symmetry to achieve system-spanning orientational order. While defect-ordered phases exist in such equilibrium materials as blue phases in liquid crystals and flux-line lattices in superconductors, our results demonstrate that motile defects in nonequilibrium active systems can attain such order while exhibiting complex spatiotemporal dynamics.

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Aligned Arrays of Nanorods, and Methods of Making and Using Them

Mechanisms of Size Control and Polymorphism in Viral Capsid Assembly

Nano Letters, Nov 1, 2008

We simulate the assembly dynamics of icosahedral capsids from subunits that interconvert between ... more We simulate the assembly dynamics of icosahedral capsids from subunits that interconvert between different conformations (or quasi-equivalent states). The simulations identify mechanisms by which subunits form empty capsids with only one morphology but adaptively assemble into different icosahedral morphologies around nanoparticle cargoes with varying sizes, as seen in recent experiments with brome mosaic virus (BMV) capsid proteins. Adaptive cargo encapsidation requires moderate cargo-subunit interaction strengths; stronger interactions frustrate assembly by stabilizing intermediates with incommensurate curvature. We compare simulation results to experiments with cowpea chlorotic mottle virus empty capsids and BMV capsids assembled on functionalized nanoparticles and suggest new cargo encapsidation experiments. Finally, we find that both empty and templated capsids maintain the precise spatial ordering of subunit conformations seen in the crystal structure even if interactions that preserve this arrangement are favored by as little as the thermal energy, consistent with experimental observations that different subunit conformations are highly similar.

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Prolonging assembly through dissociation:A self assembly paradigm in microtubules

We study a one-dimensional model of microtubule assembly and disassembly in which GTP bound to tu... more We study a one-dimensional model of microtubule assembly and disassembly in which GTP bound to tubulins within the microtubule undergoes stochastic hydrolysis. In contrast to models that consider only a cap of GTP-bound tubulin, stochastic hydrolysis allows GTP-bound tubulin remnants to exist within the microtubule. We find that these buried GTP remnants enable an alternative mechanism of recovery from shrinkage and enhances fluctuations of filament lengths. Under conditions for which this alternative mechanism dominates, an increasing depolymerization rate leads to a decrease in dissociation rate and thus a net increase in assembly.

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Allosteric Control of Icosahedral Capsid Assembly

The journal of physical chemistry. B, Jan 7, 2016

During the life cycle of a virus, viral proteins and other components self-assemble to form an or... more During the life cycle of a virus, viral proteins and other components self-assemble to form an ordered protein shell called a capsid. This assembly process is subject to multiple competing constraints, including the need to form a thermostable shell while avoiding kinetic traps. It has been proposed that viral assembly satisfies these constraints through allosteric regulation, including the interconversion of capsid proteins among conformations with different propensities for assembly. In this article, we use computational and theoretical modeling to explore how such allostery affects the assembly of icosahedral shells. We simulate assembly under a wide range of protein concentrations, protein binding affinities, and two different mechanisms of allosteric control. We find that above a threshold strength of allosteric control, assembly becomes robust over a broad range of subunit binding affinities and concentrations, allowing the formation of highly thermostable capsids. Our results...

Spontaneous Segregation of Self-Propelled Particles with Different Motilities

We study mixtures of self-propelled and passive rod-like particles in two dimensions using Browni... more We study mixtures of self-propelled and passive rod-like particles in two dimensions using Brownian dynamics simulations. The simulations demonstrate that the two species spontaneously segregate to generate a rich array of dynamical domain structures whose properties depend on the propulsion velocity, density, and composition. In addition to presenting phase diagrams as a function of the system parameters, we investigate the mechanisms driving segregation. We show that the difference in collision frequencies between self-propelled and passive rods provides a driving force for segregation, which is amplified by the tendency of the self-propelled rods to swarm or cluster. Finally, both self-propelled and passive rods exhibit giant number fluctuations for sufficient propulsion velocities.

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Virus Assembly on a Membrane is Facilitated by Membrane Microdomains

For many viruses assembly and budding occur simultaneously during virion formation. Understanding... more For many viruses assembly and budding occur simultaneously during virion formation. Understanding the mechanisms underlying this process could promote biomedical efforts to block viral propagation and enable use of capsids in nanomaterials applications. To this end, we have performed molecular dynamics simulations on a coarse-grained model that describes virus assembly on a fluctuating lipid membrane. Our simulations show that the membrane can promote association of adsorbed subunits through dimensional reduction, but also can introduce barriers that inhibit complete assembly. We find several mechanisms, including one not anticipated by equilibrium theories, by which membrane microdomains, such as lipid rafts, can enhance assembly by reducing these barriers. We show how this predicted mechanism can be experimentally tested. Furthermore, the simulations demonstrate that assembly and budding depend crucially on the system dynamics via multiple timescales related to membrane deformation, protein diffusion, association, and adsorption onto the membrane.

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Mechanisms of viral capsid assembly around a polymer

Capsids of many viruses assemble around nucleic acids or other polymers. Understanding how the pr... more Capsids of many viruses assemble around nucleic acids or other polymers. Understanding how the properties of the packaged polymer affect the assembly process could promote biomedical efforts to prevent viral assembly or nanomaterials applications that exploit assembly. To this end, we simulate on a lattice the dynamical assembly of closed, hollow shells composed of several hundred to 1000 subunits, around a flexible polymer. We find that assembly is most efficient at an optimum polymer length that scales with the surface area of the capsid; significantly longer than optimal polymers often lead to partial-capsids with unpackaged polymer `tails' or a competition between multiple partial-capsids attached to a single polymer. These predictions can be tested with bulk experiments in which capsid proteins assemble around homopolymeric RNA or synthetic polyelectrolytes. We also find that the polymer can increase the net rate of subunit accretion to a growing capsid both by stabilizing the addition of new subunits and by enhancing the incoming flux of subunits; the effects of these processes may be distinguishable with experiments that monitor the assembly of individual capsids.

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Development and Validation of the Premenstrual Symptoms Impact Survey (PMSIS): A Disease-Specific Quality of Life Assessment Tool

Http Dx Doi Org 10 1089 Jwh 2007 0377, Mar 29, 2008

To develop and validate the Premenstrual Symptoms Impact Survey (PMSIS), a brief web-based instru... more To develop and validate the Premenstrual Symptoms Impact Survey (PMSIS), a brief web-based instrument for evaluating the impact of premenstrual symptoms on health-related quality of life (HRQOL). An item bank of 68 questions was administered to a nationally representative sample of 971 women using the web, aged 18-45, who experienced regular menstrual cycles in the past 3 months, were not currently pregnant or breastfeeding, and were not being treated or taking medications for depression-related disorders in the last 2 years. Item reduction was performed using forward stepwise linear regression of an overall symptom severity score onto item scores. Three standards were used to validate the instrument: (1) the American College of Obstetricians and Gynecologists retrospective diagnostic criteria for identifying participants &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;at risk&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; for clinically significant premenstrual syndrome (PMS), (2) the American Psychiatric Association&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s Diagnostic and Statistical Manual of Mental Disorders retrospective diagnostic criteria for identifying participants at risk for premenstrual dysphoric disorder (PMDD), and (3) the Medical Outcomes Study Short Form (SF-12) Health Survey. Six items met entry criteria in the model. Approximately 6.0% of the participants were identified as being at risk for PMDD, and 17.3% were identified as being at risk for clinically significant PMS. PMSIS scale score differed significantly between participants who were and were not at risk for PMDD/clinically significant PMS. PMSIS scale score also differed significantly between participants having either high, average, or low HRQOL as defined by SF-12 physical and mental component summary scores. These results demonstrate that the PMSIS has excellent discriminative ability to detect differences in groups that are known to differ in terms of clinical criteria. The PMSIS can be used to educate consumers about the impact of their symptoms on QOL.

Coarse-grained computational studies of the assembly of viral capsids around a flexible polymer

Aps Meeting Abstracts, Mar 1, 2010

During the replication of many viruses, hundreds to thousands of protein subunits assemble around... more During the replication of many viruses, hundreds to thousands of protein subunits assemble around the viral nucleic acid to form a protein shell called a capsid. Recent electron microscopy experiments on small ssRNA viruses have shown that their enclosed RNA adopts the icosahedral symmetry of the overall capsid structure. The process that leads to this ordered encapsulation of the RNA is unknown. In this talk, we will explore dynamical simulations of coarse grained models that represent capsid proteins assembling around a flexible polymer, which shed light on the mechanisms by which icosahedral order emerges. We will discuss geometric and kinetic factors that control assembly, including the limits on the length of RNA that can be efficiently packaged. We will also report on several forms of cooperative polymer-protein motions that contribute to efficient and robust assembly. Finally, we will discuss how the simulation predictions can be tested with imaging experiments, bulk assembly kinetics measurements, and recently developed single molecule techniques that monitor the assembly of individual capsids.

Measuring cohesion between macromolecular filaments, one pair at a time: Depletion-induced microtubule bundling

In presence of non-adsorbing polymers, colloidal particles experience ubiquitous attractive inter... more In presence of non-adsorbing polymers, colloidal particles experience ubiquitous attractive interactions induced by depletion forces. Here, we measure the depletion interaction between a pair of microtubule filaments using a method that combines single filament imaging with optical trapping. By quantifying the dependence of filament cohesion on both polymer concentration and solution ionic strength, we demonstrate that the minimal model of depletion, based on the Asakura-Oosawa theory, fails to quantitatively describe the experimental data. By measuring the cohesion strength in two- and three- filament bundles we verify pairwise additivity of depletion interactions for the specific experimental conditions. The described experimental technique can be used to measure pairwise interactions between various biological or synthetic filaments and complements information extracted from bulk osmotic stress experiments.

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The Allosteric Switching Mechanism in Bacteriophage MS2

In this article we use all-atom simulations to elucidate the mechanisms underlying conformational... more In this article we use all-atom simulations to elucidate the mechanisms underlying conformational switching and allostery within the coat protein of the bacteriophage MS2. Assembly of most icosahedral virus capsids requires that the capsid protein adopt different conformations at precise locations within the capsid. It has been shown that a 19 nucleotide stem loop (TR) from the MS2 genome acts as an allosteric effector, guiding conformational switching of the coat protein during capsid assembly. Since the principal conformational changes occur far from the TR binding site, it is important to understand the molecular mechanism underlying this allosteric communication. To this end, we use all-atom simulations with explicit water combined with a path sampling technique to sample the MS2 coat protein conformational transition, in the presence and absence of TR-binding. The calculations find that TR binding strongly alters the transition free energy profile, leading to a switch in the favored conformation. We discuss changes in molecular interactions responsible for this shift. We then identify networks of amino acids with correlated motions to reveal the mechanism by which effects of TR binding span the protein. The analysis predicts amino acids whose substitution by mutagenesis could alter populations of the conformational substates or their transition rates.

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A theory for viral capsid assembly around electrostatic cores

We develop equilibrium and kinetic theories that describe the assembly of viral capsid proteins o... more We develop equilibrium and kinetic theories that describe the assembly of viral capsid proteins on a charged central core, as seen in recent experiments in which brome mosaic virus (BMV) capsids assemble around nanoparticles functionalized with polyelectrolyte. We model interactions between capsid proteins and nanoparticle surfaces as the interaction of polyelectrolyte brushes with opposite charge, using the nonlinear Poisson Boltzmann equation. The models predict that there is a threshold density of functionalized charge, above which capsids efficiently assemble around nanoparticles, and that light scatter intensity increases rapidly at early times, without the lag phase characteristic of empty capsid assembly. These predictions are consistent with, and enable interpretation of, preliminary experimental data. However, the models predict a stronger dependence of nanoparticle incorporation efficiency on functionalized charge density than measured in experiments, and do not completely capture a logarithmic growth phase seen in experimental light scatter. These discrepancies may suggest the presence of metastable disordered states in the experimental system. In addition to discussing future experiments for nanoparticle-capsid systems, we discuss broader implications for understanding assembly around charged cores such as nucleic acids.

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Atomistic Simulation of Hybridization and Melting of DNA Oligimers

Aps March Meeting Abstracts, Mar 1, 2003

Micro-devices that can detect specific DNA sequences and/or mismatches in sequences are widely us... more Micro-devices that can detect specific DNA sequences and/or mismatches in sequences are widely used in genomics applications. Many of these devices identify the hybridization of surface attached probes and solubilized DNA oligomers. In spite of the importance of such devices, little is known about the microscopic dynamics associated with hybridization. This process is very difficult to study with atomistic simulations, as even the opening or closing of one base-pair is an extremely rare event on the time scales accessible to current computers. To overcome this limitation, we have used transition path sampling to obtain a series of trajectories in which an oligomer folds and unfolds. We have identified two parameters that provide a meaningful description of the reaction: the base-base hydrogen bond energy and the number of water molecules near the bases. The dynamical trajectories are in good agreement with the free energy as a function of these coordinates, which was obtained with umbrella sampling. Namely, there are low free energy basins that correspond to the native state and the unpaired state. Furthermore, the dynamical transition states can be related to the location of saddle points in the free energy surface. We hope to use these results to improve coarse-grained models that are commonly used to study DNA melting and hybridization.

The pair potential of colloidal stars

We report on the construction of colloidal stars: 1 micrometer polystyrene beads grafted with a d... more We report on the construction of colloidal stars: 1 micrometer polystyrene beads grafted with a dense brush of 1 micrometer long and 10 nm wide semi-flexible filamentous viruses. The pair interaction potentials of colloidal stars are measured using an experimental implementation of umbrella sampling, a technique originally developed in computer simulations in order to probe rare events. The influence of ionic strength and grafting density on the interaction is measured. Good agreements are found between the measured interactions and theoretical predictions based upon the osmotic pressure of counterions.

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Spinning Straw Into Gold: Turning Academic Papers Into Commercial Fluidized Bed Reactor Solutions

This paper presents an example of academic work that has been applied in industry. A case is pres... more This paper presents an example of academic work that has been applied in industry. A case is presented of a solution to a serious operational problem involving fluidization phenomena threatening to cause structural damage to an operating chemical reactor. The process used to analyze the problem and arrive at a probable cause and design solutions are presented.

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Orientational order of motile defects in active nematics

by Gabriel S Redner, Stephen Decamp, and Michael Hagan

Nature Materials, 2015

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Dynamics and density distribution of strongly confined noninteracting nonaligning self-propelled particles in a nonconvex boundary

We study the dynamics of nonaligning, noninteracting self-propelled particles confined to a box i... more We study the dynamics of nonaligning, noninteracting self-propelled particles confined to a box in two dimensions. In the strong confinement limit, when the persistence length of the active particles is much larger than the size of the box, particles stay on the boundary and align with the local boundary normal. It is then possible to derive the steady-state density on the boundary for arbitrary box shapes. In nonconvex boxes, the nonuniqueness of the boundary normal results in hysteretic dynamics and the density is nonlocal, i.e., it depends on the global geometry of the box. These findings establish a general connection between the geometry of a confining box and the behavior of an ideal active gas it confines, thus providing a powerful tool to understand and design such confinements.

The Role of Packaging Sites in Efficient and Specific Virus Assembly

Journal of Molecular Biology, 2015

During the lifecycle of many single-stranded RNA viruses, including many human pathogens, a prote... more During the lifecycle of many single-stranded RNA viruses, including many human pathogens, a protein shell called the capsid spontaneously assembles around the viral genome. Understanding the mechanisms by which capsid proteins selectively assemble around the viral RNA amidst diverse host RNAs is a key question in virology. In one proposed mechanism, sequence elements (packaging sites) within the genomic RNA promote rapid and efficient assembly through specific interactions with the capsid proteins. In this work we develop a coarse-grained particle-based computational model for capsid proteins and RNA which represents protein-RNA interactions arising both from nonspecific electrostatics and specific packaging sites interactions. Using Brownian dynamics simulations, we explore how the efficiency and specificity of assembly depend on solution conditions (which control protein-protein and nonspecific protein-RNA interactions) as well as the strength and number of packaging sites. We identify distinct regions in parameter space in which packaging sites lead to highly specific assembly via different mechanisms, and others in which packaging sites lead to kinetic traps. We relate these computational predictions to in vitro assays for specificity in which cognate viral RNAs are compete against non-cognate RNAs for assembly by capsid proteins. * hagan@brandeis.edu arXiv:1502.05029v1 [q-bio.BM]

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Measuring cohesion between macromolecular filaments one pair at a time: depletion-induced microtubule bundling

Physical review letters, Jan 3, 2015

In the presence of nonadsorbing polymers, colloidal particles experience ubiquitous attractive in... more In the presence of nonadsorbing polymers, colloidal particles experience ubiquitous attractive interactions induced by depletion forces. Here, we measure the depletion interaction between a pair of microtubule filaments using a method that combines single filament imaging with optical trapping. By quantifying the dependence of filament cohesion on both polymer concentration and solution ionic strength, we demonstrate that the minimal model of depletion, based on the Asakura-Oosawa theory, fails to quantitatively describe the experimental data. By measuring the cohesion strength in two- and three- filament bundles, we verify pairwise additivity of depletion interactions for the specific experimental conditions. The described experimental technique can be used to measure pairwise interactions between various biological or synthetic filaments and complements information extracted from bulk osmotic stress experiments.

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