Papers by ravi radhakrishnan
Physical biology, Jan 8, 2017
Thermal fluctuations in cell membranes manifest as an excess area (Aex) which governs a multitude... more Thermal fluctuations in cell membranes manifest as an excess area (Aex) which governs a multitude of physical process at the sub-micron scale. We present a theoretical framework, based on an in silico tether pulling method, which may be used to reliably estimate Aex in live cells. We perform our simulations in two different thermodynamic ensembles: (i) the constant projected area and (ii) the constant frame tension ensembles and show the equivalence of our results in the two. The tether forces estimated from our simulations compare well with our experimental measurements for tethers extracted from ruptured GUVs and HeLa cells. We demonstrate the significance and validity of our method by showing that all our calculations performed in the initial tether formation regime (i.e., when the length of the tether is comparable to its radius) along with experiments of tether extraction in 15 different cell types collapse onto two unified scaling relationships mapping tether force, tether rad...
Physical review fluids, 2016
We have carried out direct numerical simulations (DNS) of the fluctuating Navier-Stokes equation ... more We have carried out direct numerical simulations (DNS) of the fluctuating Navier-Stokes equation together with the particle equations governing the motion of a nanosized particle or nanoparticle (NP) in a cylindrical tube. The effects of the confining boundary, its curvature, particle size, and particle density variations have all been investigated. To reveal how the nature of the temporal correlations (hydrodynamic memory) in the inertial regime is altered by the full hydrodynamic interaction due to the confining boundaries, we have employed the Arbitrary Lagrangian-Eulerian (ALE) method to determine the dynamical relaxation of a spherical NP located at various positions in the medium over a wide span of time scales compared to the fluid viscous relaxation time τv = a(2)/v, where a is the spherical particle radius and v is the kinematic viscosity. The results show that, as compared to the behavior of a particle in regions away from the confining boundary, the velocity autocorrelati...
Proceedings. Mathematical, physical, and engineering sciences, 2016
The reactive flux formalism (Chandler 1978 J. Chem. Phys.68, 2959-2970. (doi:10.1063/1.436049)) a... more The reactive flux formalism (Chandler 1978 J. Chem. Phys.68, 2959-2970. (doi:10.1063/1.436049)) and the subsequent development of methods such as transition path sampling have laid the foundation for explicitly quantifying the rate process in terms of microscopic simulations. However, explicit methods to account for how the hydrodynamic correlations impact the transient reaction rate are missing in the colloidal literature. We show that the composite generalized Langevin equation (Yu et al. 2015 Phys. Rev. E91, 052303. (doi:10.1103/PhysRevE.91.052303)) makes a significant step towards solving the coupled processes of molecular reactions and hydrodynamic relaxation by examining how the wall-mediated hydrodynamic memory impacts the two-stage temporal relaxation of the reaction rate for a nanoparticle transition between two bound states in the bulk, near-wall and lubrication regimes.
Langmuir : the ACS journal of surfaces and colloids, Jan 17, 2017
Inspired by proteins that generate membrane curvature, sense the underlying membrane geometry, an... more Inspired by proteins that generate membrane curvature, sense the underlying membrane geometry, and migrate driven by curvature gradients, we explore the question: Can colloids, adhered to lipid bilayers, also sense and respond to membrane geometry? We report the migration of Janus microparticles adhered to giant unilamellar vesicles elongated to present spatially varying curvatures. In our experiments, colloids migrate only when the membranes are tense, suggesting that they migrate to minimize membrane area. By determining the energy dissipated along a trajectory, the energy field is inferred to depend on the local deviatoric curvature, like curvature driven capillary migration on interfaces between immiscible fluids. In this latter system, energy gradients are larger, so colloids move deterministically, whereas the paths traced by colloids on vesicles have significant fluctuations. By addressing the role of Brownian motion, we show that the observed migration is analogous to curvat...
Proceedings of the National Academy of Sciences of the United States of America, Aug 30, 2016
We present coarse-grained molecular dynamics simulations of the epsin N-terminal homology domain ... more We present coarse-grained molecular dynamics simulations of the epsin N-terminal homology domain interacting with a lipid bilayer and demonstrate a rigorous theoretical formalism and analysis method for computing the induced curvature field in varying concentrations of the protein in the dilute limit. Our theory is based on the description of the height-height undulation spectrum in the presence of a curvature field. We formulated an objective function to compare the acquired undulation spectrum from the simulations to that of the theory. We recover the curvature field parameters by minimizing the objective function even in the limit where the protein-induced membrane curvature is of the same order as the amplitude due to thermal undulations. The coupling between curvature and undulations leads to significant predictions: (i) Under dilute conditions, the proteins can sense a site of spontaneous curvature at distances much larger than their size; (ii) as the density of proteins incre...
International Journal of Advances in Engineering Sciences and Applied Mathematics, 2016
The conformational free energy landscape of a system is a fundamental thermodynamic quantity of i... more The conformational free energy landscape of a system is a fundamental thermodynamic quantity of importance particularly in the study of soft matter and biological systems, in which the entropic contributions play a dominant role. While computational methods to delineate the free energy landscape are routinely used to analyze the relative stability of conformational states, to determine phase boundaries, and to compute ligand-receptor binding energies its use in problems involving the cell membrane is limited. Here, we present an overview of four different free energy methods to study morphological transitions in bilayer membranes, induced either by the action of curvature remodeling proteins or due to the application of external forces. Using a triangulated surface as a model for the cell membrane and using the framework of dynamical triangulation Monte Carlo, we have focused on the methods of Widom insertion, thermodynamic integration, Bennett acceptance scheme, and umbrella sampling and weighted histogram analysis. We have demonstrated how these methods can be employed in a variety of problems involving the cell membrane. Specifically, we have shown that the chemical potential, computed using Widom insertion, and the relative free energies, computed using thermodynamic integration and Bennett acceptance method, are excellent measures to study the transition from curvature sensing to curvature inducing behavior of membrane associated proteins. The umbrella sampling and WHAM analysis has been used to study the thermodynamics of tether formation in cell membranes and the quantitative predictions of the computational model are in excellent agreement with experimental measurements. Furthermore, we also present a method based on WHAM and thermodynamic integration to handle problems related to end-point-catastrophe that are common in most free energy methods.
Physical Review E, 2015
We investigate the phenomenon of protein induced tubulation of lipid bilayer membranes within a c... more We investigate the phenomenon of protein induced tubulation of lipid bilayer membranes within a continuum framework using Monte Carlo simulations coupled with the Widom insertion technique to compute excess chemical potentials. Tubular morphologies are spontaneously formed when the density and the curvature-field strength of the membrane bound proteins exceed their respective thresholds and this transition is marked by a sharp drop in the excess chemical potential. We find that the planar to tubular transition can be described by a micellar model and that the corresponding free energy barrier increases with increase in the curvaturefield strength, (i.e. of protein-membrane interactions), and also with increase in membrane tension.
Physical Chemistry Chemical Physics, 2015
The most highly charged phospholipids, polyphosphoinositides, are often involved in signaling pat... more The most highly charged phospholipids, polyphosphoinositides, are often involved in signaling pathways that originate at cell–cell and cell–matrix contacts, and different isomers of polyphosphoinositides have distinct biological functions that cannot be explained by separate highly specific protein ligand binding sites [Lemmon, Nat. Rev. Mol. Cell Biol., 2008, 9, 99–111].
Journal of Nanotechnology in Engineering and Medicine, 2013
This review discusses current progress and future challenges in the numerical modeling of targete... more This review discusses current progress and future challenges in the numerical modeling of targeted drug delivery using functionalized nanocarriers (NC). Antibody coated nanocarriers of various size and shapes, also called functionalized nanocarriers, are designed to be injected in the vasculature, whereby they undergo translational and rotational motion governed by hydrodynamic interaction with blood particulates as well as adhesive interactions mediated by the surface antibody binding to target antigens/receptors on cell surfaces. We review current multiscale modeling approaches rooted in computational fluid dynamics and nonequilibrium statistical mechanics to accurately resolve fluid, thermal, as well as adhesive interactions governing nanocarrier motion and their binding to endothelial cells lining the vasculature. We also outline current challenges and unresolved issues surrounding the modeling methods. Experimental approaches in pharmacology and bioengineering are discussed bri...
Handbook of Materials Modeling, 2005
Many physico-chemical processes such as nucleation events in phase transitions, chemical reaction... more Many physico-chemical processes such as nucleation events in phase transitions, chemical reactions, conformational changes of biomolecules, and protein folding are activated processes that involve rare transitions between stable or metastable states in the free energy surface. Understanding the underlying mechanism and computing the rates associated with such processes is a central to many applications. For instance, the familiar process of nucleation of ice from supercooled water is encountered in several scientific and technologically relevant processes. The formation of ice microcrystals in clouds via nucleation is a phenomenon that has a large impact in terms of governing global climatic changes. The key to the survival of Antarctic fish and certain species of beetles through harsh winters is their ability to inhibit nucleation of intracellular ice with the aid of antifreeze proteins. At the other end of the spectrum, certain protein assemblies called ice-nucleation agents are believed to be responsible for catalyzing ice nucleation, a phenomenon, which is exploited by certain bacteria to derive nutrients from their host plants. Controlling the formation and propagation of intracellular ice is finding importance in cryopreservation of natural and biosynthetic tissues. Similarly, one can cite many technologically relevant self-assembly and transport processes in the context of fabrication of advanced materials for specific applications in drug delivery, biosensing, and chemical catalysis. A unifying feature among various activated events is that they can be understood in terms of transitions between a series of stable (global minimum) 1
Physics reports, 2014
Biological membranes constitute boundaries of cells and cell organelles. These membranes are soft... more Biological membranes constitute boundaries of cells and cell organelles. These membranes are soft fluid interfaces whose thermodynamic states are dictated by bending moduli, induced curvature fields, and thermal fluctuations. Recently, there has been a flood of experimental evidence highlighting active roles for these structures in many cellular processes ranging from trafficking of cargo to cell motility. It is believed that the local membrane curvature, which is continuously altered due to its interactions with myriad proteins and other macromolecules attached to its surface, holds the key to the emergent functionality in these cellular processes. Mechanisms at the atomic scale are dictated by protein-lipid interaction strength, lipid composition, lipid distribution in the vicinity of the protein, shape and amino acid composition of the protein, and its amino acid contents. The specificity of molecular interactions together with the cooperativity of multiple proteins induce and st...
Integrative Biology, 2011
In this review, we describe the application of experimental data and modeling of intracellular en... more In this review, we describe the application of experimental data and modeling of intracellular endocytic trafficking mechanisms with a focus on the process of clathrin-mediated endocytosis. A detailed parts-list for the protein-protein interactions in clathrin-mediated endocytosis has been available for some time. However, recent experimental, theoretical, and computational tools have proved to be critical in establishing a sequence of events, cooperative dynamics, and energetics of the intracellular process. On the experimental front, total internal reflection fluorescence microscopy, photo-activated localization microscopy, and spinning-disk confocal microscopy have focused on assembly and patterning of endocytic proteins at the membrane, while on the theory front, minimal theoretical models for clathrin nucleation, biophysical models for membrane curvature and bending elasticity, as well as methods from computational structural and systems biology, have proved insightful in describing membrane topologies, curvature mechanisms, and energetics. † Electronic supplementary information (ESI) available. See
Arxiv preprint arXiv: …, 2008
The Journal of Physical Chemistry C, 2007
We present an equilibrium model for quantifying the effect of glycocalyx in mediating the interac... more We present an equilibrium model for quantifying the effect of glycocalyx in mediating the interaction of functionalized nanocarriers with endothelial cells. In this model, nanocarrier adhesion is governed by the interplay between three physical parameters, namely, glycocalyx resistance, flexural rigidity of receptors, and receptor-ligand bond stiffness. We describe a procedure to rationally determine the values of these crucial parameters based on several independent (single molecule and cell-based) characterizing experiments. Using our model and independent derivation of the parameter values in conjunction with Monte Carlo simulations, we describe the binding of nanocarriers to endothelial cells at equilibrium. We show that we can quantitatively reproduce the experimental binding affinities with zero fitting to binding data. Additionally, our simulations provide quantitative descriptions for the multivalency in nanocarrier binding, as well as for the degree of clustering of antigens. Our study identifies two interesting parameters: glycocalyx resistance and antigen flexural rigidity, both of which reduce binding of nanocarriers and alter the sensitivity of the nanocarrier binding constant to changes in temperature. Collectively, our model, parameter estimations, simulations, and sensitivity analyses help provide unified molecular and energetic analyses of the nanocarrier binding process.
PLoS Computational Biology, 2010
Physical Review Letters, 2003
We employ two-body and three-body bond-orientational order-parameters, in conjunction with non-Bo... more We employ two-body and three-body bond-orientational order-parameters, in conjunction with non-Boltzmann sampling to calculate the free energy barrier to nucleation of crystalline phases of water. We find that, as the coupling between the successive peaks of the direct correlation function increases, the free energy barrier to nucleation decreases. On this basis we explain the important parameters that govern the nucleation rate involving crystalline phases of water in different homogeneous and inhomogeneous environments, giving a ''unified picture'' of ice nucleation in water.
Physical Review Letters, 1997
For adsorbates confined within a single, sufficiently narrow cylindrical pore, no phase transitio... more For adsorbates confined within a single, sufficiently narrow cylindrical pore, no phase transitions occur because the system is too close to the one-dimensional limit. We study the influence of intermolecular correlations between adsorbed molecules in neighboring cylindrical pores, using molecular simulation. For a simple model of methane in the molecular sieve ALPO 4-5, we find that a phase transition between two fluid states ("gas" and "liquid") occurs below a critical temperature that is depressed relative to the bulk value. [S0031-9007(97)04210-5]
Molecular Physics, 2006
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Papers by ravi radhakrishnan