Prolonging assembly through dissociation

Microtubules are semiflexible polymers that serve as structural components inside the eukaryotic cell and are involved in many cellular processes such as mitosis, cytokinesis, and vesicular transport. In order to perform these functions, microtubules continually rearrange through a process known as dynamic instability, in which they switch from a phase of slow elongation to rapid shortening (catastrophe), and from rapid shortening to growth (rescue). The basic self-assembly mechanism underlying this process, assembly mediated by nucleotide phosphate activity, is omnipresent in biological systems.  A recent paper, Prolonging assembly through dissociation: A self-assembly paradigm in microtubules ,  published in the May 3 issue of Physical Review E,  presents a new paradigm for such self-assembly in which increasing depolymerization rate can enhance assembly.  Such a scenario can occur only out of equilibrium. Brandeis Physics postdoc Sumedha, working with Chakraborty and Hagan, carried out theoretical analysis of a stochastic hydrolysis model to demonstrate the effect and predict features of growth fluctuations, which should be measurable in experiments that probe microtubule dynamics at the nanoscale.

Model for microtuble dynamics. All activity is assumed to occur at the right end of the microtubule (denoted as ">")

The essential features of the model that leads to the counterintuitive result of depolymerization helping assembly are (a) stochastic hydrolysis that allows GTP to transform into GDP  in any part of the microtubule, and (b) a much higher rate of GTP attachment if the end of the microtubule has a GTP-bound tubulin dimer, compared to a GDP-bound tubulin dimer.    Process (a) leads to islands of GTP-bound tubulins to be buried deep in the microtubule.   Depolymerization from the end reveals these islands and enhances assembly because of the biased attachment rate (b).  The simplicity of the model lent itself to analytical results for various aspects of the growth statistics in particular parameter regimes.   Simulations of the model supported these analytical results, and extended them to regimes where it was not possible to solve the model analytically.  The statistics of the growth fluctuations in this stochastic hydrolysis model are very different from “cap models” which do not have GTP remnants buried inside a growing microtubule.   Testing the predictions in experiments could, therefore, lead to a better understanding of the processes underlying dynamical instability in-vivo and in-vitro.   An interesting question to explore is whether the bias in the attachment rates is different under different conditions of microtubule growth.

Physics students present research at 20th Annual Berko Symposium on May 16

On Monday, May 16, the Physics Department will hold the Twentieth Annual Student Research Symposium in Memory of Professor Stephan Berko in Abelson 131. The symposium will end with talks by the two Berko Prize winning students, undergraduate Netta Engelhardt and graduate student Tim Sanchez. The whole department then gathers for a lunch of cold cuts, cookies and conversation. “It’s a great way to close out the academic year,” said Professor of Astrophysics and Department Chair John Wardle. “We come together to celebrate our students’ research and hear what the different research groups are doing.”

The undergraduate speakers will describe their senior thesis honors research. This is the final step in gaining an honors degree in physics, and most of them will also be co-authors on a paper published in a mainline science journal. The graduate student speakers are in the middle of their PhD research, and will disucss their progress and their goals.

The prize winners are nominated and chosen by the faculty for making particularly noteworthy progress in their research. Graduate student winner Sanchez’ talk is titled “Reconstructing cilia beating from the ground up.” He works in Professor Zvonimir Dogic’s lab studying soft condensed matter. Undergraduate winner Engelhardt’s talk is titled “A New Approach to Solving the Hermitian Yang-Mills Equations”. She works with Professors Matt Headrick and Bong Lian (Math) on problems in theoretical physics and string theory. The schedule for Monday morning and abstracts of all the talks can be found on the Physics Department website.

Sanchez’ research very much represents the growing interdisciplinary nature of science at Brandeis. Here, a physicist’s approach is used to study a biological organism. Professor Zvonimir Dogic says of his work “He has made a whole series of important discoveries that are going to have a measurable impact on a number of diverse fields ranging from cell biology, biophysics, soft matter physics and non-equilibrium statistical mechanics.  His discoveries have fundamentally transformed the direction of my laboratory and probably of many other laboratories as well.”

Engelhardt’s research is much more abstract and mathematical, and concerns fundamental problems in string theory, not usually an area tackled by undergraduates. Professor Headrick says “Netta really, really wants to be a theoretical physicist, preferably a string theorist. She has a passion for mathematics, physics, and the connections between them.” He adds that she is utterly fearless in tackling hard problems. Netta has been awarded an NSF Graduate Research Fellowship based on her undergraduate work here.  Next year she will enter graduate school at UC Santa Barbara and will likely work with eminent string theorist Gary Horowitz, who has already supervised the PhD research of two other Brandeis physics alumni, Matthew Roberts ’05, and Benson Way ’08.

This Student Research Symposium is now in its 20th year. The “First Annual…..” (two words which are always unwise to put next to each other) was initiated in 1992 by Wardle to honor Professor Stephan Berko, who had died suddenly the previous year. Family, friends and colleagues contributed to a fund to support and celebrate student research in his memory. This provides the prize money which Netta and Tim will share.

Stephan Berko was a brilliant and volatile experimental physicist who was one of the founding members of the physics department. He was born in Romania in 1924 and was a survivor of both the Auschwitz and Dachau concentration camps. He came to the United States under a Hillel Foundation scholarship and obtained his PhD at the University of Virginia. He came to Brandeis in 1961 to establish a program in experimental physics and worked tirelessly to build up the department. Together with Professors Karl Canter (dec. 2006) and Alan Mills (now at UC Riverside) he established Brandeis as a world center for research into positrons (the anti-matter mirror image of ordinary electrons). In a series of brilliant experiments they achieved many “firsts,” culminating in election to the National Academy of Sciences for Steve, and, it has been rumored, in a Nobel Prize nomination for the three of them. Steve was as passionate about teaching as he was about research, and when he died, it seemed most appropriate to honor his memory by celebrating the research of our graduate and undergraduate students. During the coffee break on Monday, we will show a movie of Steve lecturing on “cold fusion,” a headline-grabbing but phony claim for producing cheap energy from 1989.

Molecular mechanisms of noisy transcription

In a recently published paper “Effect of promoter architecture on the cell-to-cell variability in gene expression” in PLoS Computational Biology, Alvaro Sanchez and co-workers investigated how the architecture of a model promoter region (characterized by number of transcription factor binding sites, the binding affinity and spacing on the DNA) affects the way in which individual cells respond to environmental stimuli. In particular, they examine, using stochastic chemical kinetics, how the intrinsic randomness in the binding and unbinding of transcription factors to their binding sites generates cell-to-cell differences in transcript and protein levels within a population. The analysis uses a combination of computational modeling and analytical mathematical methods. Sanchez, a recent Ph.D. graduate in Biophysics and Structural Biology performed this work with Jané Kondev (Physics), and in collaboration with Rob Phillips, Hernan Garcia and Daniel Jones (Caltech).

While previous population-average models explained well how promoter architecture affects the average response of a population of cells to changes in the concentration of transcription factors, the question of how the response of individual cells is determined by promoter region sequence remains generally unsolved and limited to simplified coarse-grain models. By way of an example, the authors of this study investigated the effect of cooperative binding between transcription factors in the level of variability in the transcriptional response to increasing concentrations of those factors. It is well known that cooperativity in gene regulation increases the sensitivity of the response of the promoter to changes in the intracellular concentration of transcription factors, leading to a switch-like response. By examining this architecture, Sanchez and co-workers found that cooperativity is also a source of large intrinsic cell-to-cell variability in gene expression: larger sensitivity comes accompanied with larger variability (even if all cells contain the exact same amount of repressor).

This investigation continues a collaboration between theorists at Brandeis and experimentalists at Caltech, which aims to connect the biochemical, molecular understanding of transcriptional regulation coming from in vitro biochemical experiments (which are also being done in the Gelles lab at Brandeis) with the phenotypic behavior of individual cells as determined by gene expression measurements in single live cells. Many of the predictions of this computational study are currently being tested in Rob Phillips’ lab.


Barry and Dogic receive 2010 Cozzarelli Prize

Physics graduate student Edward Barry and Professor Zvonimir Dogic have been selected to receive the 2010 Cozzarelli Prize in Engineering and Applied Sciences from the Proceedings of the National Academy of Sciences (PNAS) for their work entitled “Entropy driven self-assembly of non-amphiphilic colloidal membranes.”

The work of Barry and Dogic was selected for exploring a novel pathway for the self-assembly of 2D fluid-like surfaces or monolayer membranes from non-amphiphilic molecules. Amphiphilic molecules consist of immiscible components, such as a hydrophobic tail and a hydrophilic head, which are irreversibly linked to each other, thus frustrating their bulk separation. When added to water, these molecules self-assemble into a variety of structures in order to satisfy competing affinities for the solvent. One particular structure, a bilayer membrane, which is a thin flexible sheet with remarkable mechanical and chemical properties, plays an essential role in biology, physics, and material science. Over the past decade the paramount example of conventional amphiphilic self-assembly has inspired the synthesis of numerous amphiphilic-type building blocks for studies of membrane self-assembly including various block-copolymers, heterogeneous nanorods, and hybrid protein-polymer complexes. Underlying all of these studies is the belief that amphiphilic molecules are an essential requirement for membrane assembly.

Barry and Dogic, using a combination of theory and experiments, describe for the first time a set of design principles required for the assembly of non-amphiphilic membranes in which the constituent rod-like molecules are chemically homogeneous.  Using a simple mixture of filamentous bacteriophages and non-adsorbing polymer, they were able to assemble macroscopic membranes roughly 4-5 orders of magnitude larger than the constituent molecules themselves. Due to unique properties of their system, Barry and Dogic were able to characterize the physical behavior of the resulting non-amphiphilic membranes at all relevant length scales and provide an entropic mechanism that explains their stability. The importance of these results lies in their potential to establish a fundamentally different route toward solution based self-assembly of 2D materials.

Papers selected for the Cozzarelli Prize were chosen from more than 3,700 research articles published by PNAS in 2010 and represent the six broadly defined classes under which the National Academy of Sciences is organized. The award was established in 2005 and named the Cozzarelli Prize in 2007 to honor late PNAS Editor-in-Chief Nicholas R. Cozzarelli. The annual award acknowledges recently published papers that reflect scientific excellence and originality. The 2010 awards will be presented at the PNAS Editorial Board Meeting, and awardees are recognized at the awards ceremony, during the National Academy of Sciences Annual Meeting on May 1, 2011, in National Harbor, Maryland.

Biochemistry, Biophysics and Quantitative Biology Retreat 2010

Grad students, postdocs and faculty from the Graduate Program in Biochemistry & Biophysics and from the interdisciplinary program in Quantitative Biology gathered for their Annual Retreat October 21-22, 2010 at Marine Biological Laboratory in Woods Hole, MA. See the program here.

Chirality leads to self-limited self-assembly

Simple building blocks that self-assemble into ordered structures with controlled sizes are essential for nanomaterials applications, but what are the general design principles for molecules that undergo self-terminating self-assembly? The question is addressed in a recent paper in Physical Review Letters by Yasheng Yang, graduate student in Physics, working together with Profs. Meyer and Hagan,  The paper considers molecules that self assemble to form filamentous bundles, and shows that chirality, or asymmetry with respect to a molecule’s mirror image, can result in stable self-limited structures. Using modern computational techniques, the authors demonstrate that chirality frustrates long range order and thereby terminates assembly upon formation of regular self-limited bundles.  With strong interactions, however, the frustration is relieved by defects, which give rise to branched networks or irregular bundles.

Figure: (a) Snapshots of regular chiral bundles. Free energy calculations and dynamics demonstrate that the optimal diameter decreases with increasing chirality. (b) Branched bundles form with strong interactions

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