Phillip L Geissler

University of California, Berkeley, Berkeley, California, United States

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Publications (106)682.39 Total impact

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    Todd R. Gingrich, Phillip L. Geissler
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    ABSTRACT: Importance sampling of trajectories has proved a uniquely successful strategy for exploring rare dynamical behaviors of complex systems in an unbiased way. Carrying out this sampling, however, requires an ability to propose changes to dynamical pathways that are substantial, yet sufficiently modest to obtain reasonable acceptance rates. Satisfying this requirement becomes very challenging in the case of long trajectories, due to the characteristic divergences of chaotic dynamics. Here we examine schemes for addressing this problem, which engineer correlation between a trial trajectory and its reference path, for instance using artificial forces. Our analysis is facilitated by a modern perspective on Markov Chain Monte Carlo sampling, inspired by non-equilibrium statistical mechanics, which clarifies the types of sampling strategies that can scale to long trajectories. Viewed in this light, the most promising such strategy guides a trial trajectory by manipulating the sequence of random numbers that advance its stochastic time evolution, as done in a handful of existing methods. In cases where this "noise guidance" synchronizes trajectories effectively, such as the Glauber dynamics of a two-dimensional Ising model, we show that efficient path sampling can be performed even for very long trajectories.
  • Kateri H DuBay, Gregory R Bowman, Phillip L Geissler
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    ABSTRACT: Conspectus Folded protein structures are both stable and dynamic. Historically, our clearest window into these structures came from X-ray crystallography, which generally provided a static image of each protein's singular "folded state", highlighting its stability. Deviations away from that crystallographic structure were difficult to quantify, and as a result, their potential functional consequences were often neglected. However, several dynamical and statistical studies now highlight the structural variability that is present within the protein's folded state. Here we review mounting evidence of the importance of these structural rearrangements; both experiment and computation indicate that folded proteins undergo substantial fluctuations that can greatly influence their function. Crucially, recent studies have shown that structural elements of proteins, especially their side-chain degrees of freedom, fluctuate in ways that generate significant conformational heterogeneity. The entropy associated with these motions contributes to the folded structure's thermodynamic stability. In addition, since these fluctuations can shift in response to perturbations such as ligand binding, they may play an important role in the protein's capacity to respond to environmental cues. In one compelling example, the entropy associated with side-chain fluctuations contributes significantly to regulating the binding of calmodulin to a set of peptide ligands. The neglect of fluctuations within proteins' native states was often justified by the dense packing within folded proteins, which has inspired comparisons with crystalline solids. Many liquids, however, can achieve similarly dense packing yet fluidity is maintained through correlated molecular motions. Indeed, the studies we discuss favor comparison of folded proteins not with solids but instead with dense liquids, where the internal side chain fluidity is facilitated by collective motions that are correlated over long distances. These correlated rearrangements can enable allosteric communication between different parts of a protein, through subtle and varied channels. Such long-range correlations appear to be an innate feature of proteins in general, manifest even in molecules lacking known allosteric regulators and arising robustly from the physical nature of their internal environment. Given their ubiquity, it is only to be expected that, over time, nature has refined some subset of these correlated motions and put them to use. Native state fluctuations increasingly appear to be vital for proteins' natural functions. Understanding the diversity, origin, and range of these rearrangements may provide novel routes for rationally manipulating biomolecular activity.
    Accounts of Chemical Research 02/2015; 48(4). DOI:10.1021/ar500351b · 24.35 Impact Factor
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    ABSTRACT: In a stochastic heat engine driven by a cyclic non-equilibrium protocol, fluctuations in work and heat give rise to a fluctuating efficiency. Using computer simulations and tools from large deviation theory, we have examined these fluctuations in detail for a model two-state engine. We find in general that the form of efficiency probability distributions is similar to those described by Verley et al. [arXiv:1404.3095 (2014)], in particular featuring a local minimum in the long-time limit. In contrast to the time-symmetric engine protocols studied previously, however, this minimum need not occur at the value characteristic of a reversible Carnot engine. Furthermore, while the local minimum may reside at the global minimum of a large deviation rate function, it does not generally correspond to the least likely efficiency measured over any finite time.
    New Journal of Physics 09/2014; 16(10). DOI:10.1088/1367-2630/16/10/102003 · 3.67 Impact Factor
  • Phillip L. Geissler
    ChemInform 08/2014; 45(32). DOI:10.1002/chin.201432266
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    ABSTRACT: Photoautotrophic organisms efficiently regulate absorption of light energy to sustain photochemistry while promoting photoprotection. Photoprotection is achieved in part by triggering a series of dissipative processes termed non-photochemical quenching (NPQ), which depend on the re-organization of photosystem (PS) II supercomplexes in thylakoid membranes. Using atomic force microscopy, we characterized the structural attributes of grana thylakoids from Arabidopsis thaliana to correlate differences in PSII organization with the role of SOQ1, a recently discovered thylakoid protein that prevents formation of a slowly reversible NPQ state. We developed a statistical image analysis suite to discriminate disordered from crystalline particles and classify crystalline arrays according to their unit cell properties. Through detailed analysis of the local organization of PSII supercomplexes in ordered and disordered phases, we found evidence that interactions among light-harvesting antenna complexes are weakened in the absence of SOQ1, inducing protein rearrangements that favor larger separations between PSII complexes in the majority (disordered) phase and reshaping the PSII crystallization landscape. The features we observe are distinct from known protein rearrangements associated with NPQ, providing further support for a role of SOQ1 in a novel NPQ pathway. The particle clustering and unit cell methodology developed here is generalizable to multiple types of microscopy and will enable unbiased analysis and comparison of large data sets.
    PLoS ONE 07/2014; 9(7):e101470. DOI:10.1371/journal.pone.0101470 · 3.53 Impact Factor
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    ABSTRACT: We solve a simple model that supports a dynamic phase transition and show conditions for the existence of the transition. Using methods of large deviation theory we analytically compute the joint rate function for activity and entropy production rates of the trajectories on a large ring with a single heterogeneous link. The joint rate function demonstrates two dynamical phases - one localized and the other delocalized, but the marginal rate functions do not always exhibit the underlying transition. We discuss how symmetries in dynamic order parameters influence the transition, such that distributions for certain dynamic order parameters need not reveal an underlying bistability. We discuss the implications of the transition on the response of bacterial cells to antibiotic treatment, arguing that even the simple models of a cell cycle lacking an explicit bistability will exhibit a bistability of dynamical phases.
    Physical Review E 06/2014; 90(4-1). DOI:10.1103/PhysRevE.90.042123 · 2.33 Impact Factor
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    Michael Grünwald, Phillip L Geissler
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    ABSTRACT: Nanoparticles with "sticky patches" have long been proposed as building blocks for the self-assembly of complex structures. The synthetic realizability of such patchy particles, however, greatly lags behind predictions of patterns they could form. Using computer simulations, we show that structures of the same genre can be obtained from a solution of simple isotropic spheres, provided control only over their sizes and a small number of binding affinities. In a first step, finite clusters of well-defined structure and composition emerge from natural dynamics with high yield. In effect a kind of patchy particle, these clusters can further assemble into a variety of complex superstructures, including filamentous networks, ordered sheets, and highly porous crystals.
    ACS Nano 05/2014; 8(6). DOI:10.1021/nn500978p · 12.03 Impact Factor
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    Antonia S J S Mey, Phillip L Geissler, Juan P Garrahan
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    ABSTRACT: We explore the dynamical large deviations of a lattice heteropolymer model of a protein by means of path sampling of trajectories. We uncover the existence of nonequilibrium dynamical phase transitions in ensembles of trajectories between active and inactive dynamical phases, whose nature depends on the properties of the interaction potential. We consider three potentials: two heterogeneous interaction potentials and a homogeneous Gō potential. When preserving the full heterogeneity of interactions due to a given amino acid sequence, either in a fully interacting model or in a native contacts interacting model (heterogeneous Gō model), the observed dynamic transitions occur between equilibrium highly native states and highly native but kinetically trapped states. A native activity is defined that allows us to distinguish these dynamic phases. In contrast, for the homogeneous Gō model, where all native interaction energies are uniform and the amino acid sequence plays no role, the dynamical transition is a direct consequence of the static bistability between the unfolded and the native state. In the two heterogeneous interaction models the native-active and native-inactive states, despite their thermodynamic similarity, have widely varying dynamical properties, and the transition between them occurs even in lattice proteins whose sequences are designed to make them optimal folders.
    Physical Review E 03/2014; 89(3-1):032109. DOI:10.1103/PhysRevE.89.032109 · 2.33 Impact Factor
  • Gregory R Bowman, Phillip L Geissler
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    ABSTRACT: Basic principles of statistical mechanics require that proteins sample an ensemble of conformations at any nonzero temperature. However, it is still common to treat the crystallo-graphic structure of a protein as the structure of its native state, largely because high-resolution structural characterization of protein flexibility remains a profound challenge. To as-sess the typical degree of conformational heterogeneity within folded proteins, we construct Markov state models describing the thermodynamics and kinetics of proteins ranging from 72 to 263 residues in length. Each of these models is built from hundreds of microseconds of atomically detailed molecular dynamics simulations. Examination of the side-chain degrees of freedom reveals that almost every residue visits at least two rotameric states over this time frame, with rotamer transition rates spanning a wide range of timescales (from nanoseconds to tens of microseconds). We also report substantial backbone dynamics on timescales longer than are typically addressed by experimental measures of protein flexibility, such as NMR or-der parameters. Finally, we demonstrate that these extensive rearrangements are consistent with NMR and crystallographic data, which supports the validity of our models. Altogether, the-se results depict the interior of proteins not as well-ordered solids, as is often imagined, but instead as dense fluids, which undergo substantial structural fluctuations despite their high packing fraction.
    The Journal of Physical Chemistry B 02/2014; 118(24). DOI:10.1021/jp4105823 · 3.38 Impact Factor
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    Suriyanarayanan Vaikuntanathan, Phillip L Geissler
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    ABSTRACT: The physics of air-water interfaces plays a central role in modern theories of the hydrophobic effect. Implementing these theories, however, has been hampered by the difficulty of addressing fluctuations in the shape of such soft interfaces. We show that this challenge is a fundamental consequence of mapping long wavelength density variations onto discrete degrees of freedom. Drawing from studies of surface roughness in lattice models, we account for the resulting nonlinearities simply but accurately. Simulations show that this approach captures complex solvation behaviors quantitatively.
    Physical Review Letters 01/2014; 112(2):020603. DOI:10.1103/PhysRevLett.112.020603 · 7.73 Impact Factor
  • Biophysical Journal 01/2014; 106(2):800a. DOI:10.1016/j.bpj.2013.11.4384 · 3.83 Impact Factor
  • Gregory R. Bowman, Phillip L. Geissler, Susan Marqusee
    Biophysical Journal 01/2014; 106(2):647a. DOI:10.1016/j.bpj.2013.11.3581 · 3.83 Impact Factor
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    Asaph Widmer-Cooper, Phillip L Geissler
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    ABSTRACT: We present the first nearly atomistic molecular dynamics study of nanorod-nanorod association in explicit solvent, showing that inter-rod forces can be dominated by microscopic factors absent in common continuum descriptions. Specifically, we find that alkane ligands on faceted CdS nanorods in n-hexane undergo a temperature-dependent order-disorder transition akin to that of self-assembled monolayers on macroscopic substrates. This collective ligand alignment organizes nearby solvent molecules, strongly influencing the statistics of rod-rod separation. The strong temperature-dependence of this mechanism could be exploited in the laboratory to manipulate and optimize the assembly of ordered structures.
    Nano Letters 12/2013; 14(1). DOI:10.1021/nl403067p · 12.94 Impact Factor
  • Anna R Schneider, Phillip L Geissler
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    ABSTRACT: Photosystem II (PSII) and its associated light-harvesting complex II (LHCII) are highly concentrated in the stacked grana regions of photosynthetic thylakoid membranes. PSII-LHCII supercomplexes can be arranged in disordered packings, ordered arrays, or mixtures thereof. The physical driving forces underlying array formation are unknown, complicating attempts to determine a possible functional role for arrays in regulating light harvesting or energy conversion efficiency. Here, we introduce a coarse-grained model of protein interactions in coupled photosynthetic membranes, focusing on just two particle types that feature simple shapes and potential energies motivated by structural studies. Reporting on computer simulations of the model's equilibrium fluctuations, we demonstrate its success in reproducing diverse structural features observed in experiments, including extended PSII-LHCII arrays. Free energy calculations reveal that the appearance of arrays marks a phase transition from the disordered fluid state to a system-spanning crystal. The predicted region of fluid-crystal coexistence is broad, encompassing much of the physiologically relevant parameter regime; we propose experiments that could test this prediction. Our results suggest that grana membranes lie at or near phase coexistence, conferring significant structural and functional flexibility to this densely packed membrane protein system.
    Biophysical Journal 09/2013; 105(5):1161-70. DOI:10.1016/j.bpj.2013.06.052 · 3.83 Impact Factor
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    ABSTRACT: We analyze the probability distribution for entropy production rates of trajectories evolving on a class of out-of-equilibrium kinetic networks. These networks can serve as simple models for driven dynamical systems, which are of particular importance in biological processes, where energy fluxes typically result in non-equilibrium dynamics. By analyzing the fluctuations in the entropy production, we demonstrate the emergence, in a large system size limit, of a dynamic phase transition between two distinct dynamical regimes.
    Physical Review E 07/2013; 89(6). DOI:10.1103/PhysRevE.89.062108 · 2.33 Impact Factor
  • Phillip L Geissler
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    ABSTRACT: Liquid water consistently expands our appreciation of the rich statistical mechanics that can emerge from simple molecular constituents. Here I review several interrelated areas of recent work on aqueous systems that aim to explore and explain this richness by revealing molecular arrangements, their thermodynamic origins, and the timescales on which they change. Vibrational spectroscopy of OH stretching features prominently in these discussions, with an emphasis on efforts to establish connections between spectroscopic signals and statistics of intermolecular structure. For bulk solutions, the results of these efforts largely verify and enrich existing physical pictures of hydrogen-bond network connectivity, dynamics, and response. For water at interfaces, such pictures are still emerging. As an important example I discuss the solvation of small ions at the air-water interface, whose surface propensities challenge a basic understanding of how aqueous fluctuations accommodate solutes in heterogeneous environments. Expected final online publication date for the Annual Review of Physical Chemistry Volume 64 is March 31, 2013. Please see for revised estimates.
    Annual Review of Physical Chemistry 01/2013; DOI:10.1146/annurev-physchem-040412-110153 · 15.68 Impact Factor
  • Biophysical Journal 01/2013; 104(2):654-. DOI:10.1016/j.bpj.2012.11.3611 · 3.83 Impact Factor
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    ABSTRACT: The adsorption behavior of ions at liquid-vapor interfaces exhibits several unexpected yet generic features. In particular, energy and entropy are both minimum when the solute resides near the surface, for a variety of ions in a range of polar solvents, contrary to predictions of classical theories. Motivated by this generality, and by the simple physical ingredients implicated by computational studies, we have examined interfacial solvation in highly schematic models, which resolve only coarse fluctuations in solvent density and cohesive energy. Here we show that even such lattice gas models recapitulate surprising thermodynamic trends observed in detailed simulations and experiments. Attention is focused on the case of two dimensions, for which approximate energy and entropy profiles can be calculated analytically. Simulations and theoretical analysis of the lattice gas highlight the role of capillary wave-like fluctuations in mediating adsorption. They further point to ranges of temperature and solute-solvent interaction strength where surface propensity is expected to be strongest.
    Faraday Discussions 01/2013; 160:63-74; discussion 103-20. DOI:10.1039/C2FD20106B · 4.19 Impact Factor
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    Anna R Schneider, Phillip L Geissler
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    ABSTRACT: Coarse-grained simulation is a powerful and well-established suite of computational methods for studying structure and dynamics in nanoscale biophysical systems. As our understanding of the plant photosynthetic apparatus has become increasingly nuanced, opportunities have arisen for coarse-grained simulation to complement experiment by testing hypotheses and making predictions. Here, we give an overview of best practices in coarse-grained simulation, with a focus on techniques and results that are applicable to the plant thylakoid membrane-protein system. We also discuss current research topics for which coarse-grained simulation has the potential to play a key role in advancing the field.
    Frontiers in Plant Science 01/2013; 4:555. DOI:10.3389/fpls.2013.00555 · 3.64 Impact Factor
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    ABSTRACT: Curved membranes are an essential feature of dynamic cellular structures, including endocytic pits, filopodia protrusions and most organelles. It has been proposed that specialized proteins induce curvature by binding to membranes through two primary mechanisms: membrane scaffolding by curved proteins or complexes; and insertion of wedge-like amphipathic helices into the membrane. Recent computational studies have raised questions about the efficiency of the helix-insertion mechanism, predicting that proteins must cover nearly 100% of the membrane surface to generate high curvature, an improbable physiological situation. Thus, at present, we lack a sufficient physical explanation of how protein attachment bends membranes efficiently. On the basis of studies of epsin1 and AP180, proteins involved in clathrin-mediated endocytosis, we propose a third general mechanism for bending fluid cellular membranes: protein-protein crowding. By correlating membrane tubulation with measurements of protein densities on membrane surfaces, we demonstrate that lateral pressure generated by collisions between bound proteins drives bending. Whether proteins attach by inserting a helix or by binding lipid heads with an engineered tag, protein coverage above ~20% is sufficient to bend membranes. Consistent with this crowding mechanism, we find that even proteins unrelated to membrane curvature, such as green fluorescent protein (GFP), can bend membranes when sufficiently concentrated. These findings demonstrate a highly efficient mechanism by which the crowded protein environment on the surface of cellular membranes can contribute to membrane shape change.
    Nature Cell Biology 08/2012; 14(9):944-9. DOI:10.1038/ncb2561 · 20.06 Impact Factor

Publication Stats

5k Citations
682.39 Total Impact Points


  • 1999–2015
    • University of California, Berkeley
      • Department of Chemistry
      Berkeley, California, United States
  • 2005–2013
    • Lawrence Berkeley National Laboratory
      • Materials Sciences Division
      Berkeley, California, United States
    • Columbia University
      • Department of Chemistry
      New York, New York, United States
  • 2008
    • Stanford University
      Palo Alto, California, United States
  • 2006–2008
    • CSU Mentor
      Long Beach, California, United States
  • 2003–2004
    • Massachusetts Institute of Technology
      • Department of Chemistry
      Cambridge, MA, United States
  • 2001–2002
    • Harvard University
      • Department of Chemistry and Chemical Biology
      Boston, MA, United States