Frank L. H. Brown

Implicit solvent simulation models for biomembranes

Fully atomic simulation strategies are infeasible for the study of many processes of interest to membrane biology, biophysics and biochemistry. We review various coarse-grained simulation methodologies with special emphasis on methods and models that do not require the explicit simulation of water. Examples from our own research demonstrate that such models have potential for simulating a variety of biologically relevant phenomena at the membrane surface.

Elastic Modeling of Biomembranes and Lipid Bilayers

The simulation of biological membranes over length and time scales relevant to cellular biology is not currently feasible using conventional (fully atomic or molecularly detailed) simulation strategies. Given the wide disparity between what is possible on todays computers and the problems one might like to study, it seems unlikely this situation will change for several decades. An appealing alternative to traditional computational approaches is to employ simpler, continuum-based models developed within the frameworks of elasticity theory, fluid dynamics, and statistical mechanics. Although such models have seen wide use in analytical descriptions of membrane behavior, the extension of these methods to more general situations and numerical analysis is just beginning to be explored. This article reviews continuum models for membrane behavior with an emphasis on the use of such models in computational studies. Two applications are explored to demonstrate the utility of this level of coarse-grained modeling.

Solvent-free simulations of fluid membrane bilayers

A molecular level model for lipid bilayers is presented. Lipids are represented by rigid, asymmetric, soft spherocylinders in implicit solvent. A simple three parameter potential between pairs of lipids gives rise to a rich assortment of phases including (but not limited to) micelles, fluid bilayers, and gel-like bilayers. Monte Carlo simulations have been carried out to verify self-assembly, characterize the phases corresponding to different potential parametrizations, and to quantify the physical properties associated with those parameter sets corresponding to fluid bilayer behavior. The studied fluid bilayers have compressibility moduli in agreement with experimental systems, but display bending moduli at least three times larger than typical biological membranes without cholesterol.

Membrane-Protein Interactions in a Generic Coarse-Grained Model for Lipid Bilayers

We study membrane-protein interactions and membrane-mediated protein-protein interactions by Monte Carlo simulations of a generic coarse-grained model for lipid bilayers with cylindrical hydrophobic inclusions. The strength of the hydrophobic force and the hydrophobic thickness of the proteins are systematically varied. The results are compared with analytical predictions of two popular analytical theories: The Landau-de Gennes theory and the elastic theory. The elastic theory provides an excellent description of the fluctuation spectra of pure membranes and successfully reproduces the deformation profiles of membranes around single proteins. However, its prediction for the potential of mean force between proteins is not compatible with the simulation data for large distances. The simulations show that the lipid-mediated interactions are governed by five competing factors: direct interactions; lipid-induced depletion interactions; lipid bridging; lipid packing; and a smooth long-range contribution. The mechanisms leading to hydrophobic mismatch interactions are critically analyzed.

Thermal fluctuations in shape, thickness, and molecular orientation in lipid bilayers

We present a unified continuum-level model for bilayer energetics that includes the effects of bending, compression, lipid orientation (tilting relative to the monolayer surface normal), and microscopic noise (protrusions). Expressions for thermal fluctuation amplitudes of several physical quantities are derived. These predictions are shown to be in good agreement with molecular simulations.

Interpreting Membrane Scattering Experiments at the Mesoscale: The Contribution of Dissipation within the Bilayer

Neutron spin-echo spectroscopy provides a means to study membrane undulation dynamics over length scales roughly spanning 10-100 nanometers. Modern interpretation of these measurements relies on the theoretical predictions of Zilman and Granek; however, it is necessary to introduce an anomalously large solvent viscosity within this theory to obtain quantitative agreement with experiment. An extended theoretical treatment is presented that includes the effects of internal dissipation within the bilayer. Within the length and time regimes appropriate to neutron spin-echo experiments, the results of Zilman and Granek are largely recovered, except that the bilayer curvature modulus kappa appearing in their theory must be replaced with an effective dynamic curvature modulus kappa =kappa+2d(2)k(m), where d is a distance comparable to the monolayer thickness (the height of the neutral surface from bilayer midplane) and k(m) is the monolayer compressibility modulus. Direct comparison between theory and experiment becomes possible without any rescaling of physical parameters.

Continuum simulations of biomembrane dynamics and the importance of hydrodynamic effects.

Traditional particle-based simulation strategies are impractical for the study of lipid bilayers and biological membranes over the longest length and time scales (microns, seconds and longer) relevant to cellular biology. Continuum-based models developed within the frameworks of elasticity theory, fluid dynamics and statistical mechanics provide a framework for studying membrane biophysics over a range of mesoscopic to macroscopic length and time regimes, but the application of such ideas to simulation studies has occurred only relatively recently. We review some of our efforts in this direction with emphasis on the dynamics in model membrane systems. Several examples are presented that highlight the prominent role of hydrodynamics in membrane dynamics and we argue that careful consideration of fluid dynamics is key to understanding membrane biophysics at the cellular scale.

Nonequilibrium membrane fluctuations driven by active proteins

We extend a model for nonthermal membrane undulations driven by active (adenosine triphosphate-dependent or light-harvesting) membrane proteins [N. Gov, Phys. Rev. Lett. 93, 268104 (2004)]. The present model accounts for the fact that proteins can diffuse laterally across the membrane surface and that individual proteins are expected to exert forces preferentially in one normal direction over the other (due to their orientation within the bilayer). The addition of these effects alters the scaling of fluctuation amplitudes with system size. Additionally, theoretical arguments and dynamic simulations both suggest that, in certain regimes, the probability distribution of fluctuation amplitudes is expected to be non-Gaussian (in contrast to thermal systems).

Photon emission from driven single molecules

The detection of photons emitted from a single molecule under the influence of electromagnetic radiation is considered. Utilizing a generating function formalism, we derive several exact results for the statistics of such emitted photons within the framework of the temporally modulated optical Bloch equations. Additionally, it is shown how these results reduce to previously obtained limiting behaviors. An appealing feature of this formulation is the inclusion of both photon bunching and anti-bunching effects within a single theoretical framework that is well suited for numerical analysis. Several examples are considered to demonstrate the feasibility of the approach in calculations. In most cases, these results verify known phenomena. In one case, we report a result that was missed by prior approximate treatments. This new effect centers around the fact that a chromophore will display anti-bunching behavior in the limit of fast modulation of the resonant absorption frequency.

Single molecule photon emission statistics for non-Markovian blinking models

The statistics of photon emission from a single molecule under continuous wave excitation are considered. In particular, we study stochastic model systems where photon emission rates evolve in time with non-Markovian dynamics. Our calculations are based on the recently introduced generalized optical Bloch equation (GBE) formalism, but with numerical complications beyond those seen in previous Markovian stochastic models. A spectral representation is introduced to facilitate the numerical solution of the GBE equations for these more challenging cases.