Research Interest: We develop and use multiscale theories and molecular simulations tools
and apply ideas/concepts from statistical mechanics and condensed matter physics to
understand the behavior of complex biological systems. Our primary focus is in the field of
membrane biophysics. Specific research directions include:
Plasma membrane is a complex self-assembly of a variety of lipids, sterols and proteins. Differential molecular interactions among these diverse constituents give rise to spatial and dynamic heterogeneities in the membrane structure. These sub-100 nm transient structures, which are stabilized far away from equilibrium, are believed to be functionally important in various physiological processes of the cell ranging from cell growth and movement to signal transduction and intercellular transport of proteins. Using advance molecular simulations techniques and ideas/concepts from statistical mechanics and condensed matter physics, we are trying to address a few fundamental questions in the field of membrane spatiotemporal organization. This includes exploring the evolutionary rationale behind maintaining such complex lipid diversity despite the high metabolic expense of lipid homeostasis and identifying the build-in degeneracy in the membrane organization vis-à-vis related functionalities.
Biological membranes undergo dramatic changes in curvature/shape during process such as endocytosis, infection, immune response, the formation of organelles and division. These dynamic vesicular transport processes are often accompanied by tightly regulated leakage-free membrane fusion/fission reactions. Though topologically reversed, both reactions require that two bilayers are brought in close proximity against very high activation (hydration) energy barriers and possibly pass through several non-bilayer intermediates. The coupling between the conformation changes in the protein machinery and the orderly rearrangements of lipids leads to extreme membrane remodeling. The experimental difficulties associated with capturing the short-lived intermediates in protein conformations and membrane topologies point to the requirement for high-fidelity multiscale simulations. Currently, we are exploring the molecular mechanisms underlying the dynamin-assisted fission and Env-mediated HIV-1 fusion processes. We plan to apply the tools developed in the lab to explore the sub-millisecond kinetics and intermediates in complex vesicular transport processes such as those found in Golgi and Endoplasmic Reticulum.
In vivo mechanical forces, much like biochemical and electric signals, possess distinguishable features (magnitude, frequency, mode (steady/pulsatile), type (laminar/turbulent), orientation and duration), which can be diagnosed by specific biological machinery. Gating processes in ion-channels and activation of focal adhesion (FA) proteins at the cell-matrix interface are some examples of stress-activated systems of interest for us. The force-induced conformational changes are intrinsically nonequilibrium in nature and non-trivial to model. Currently, we are using large-scale molecular simulations with advance-sampling techniques to understand the polymodal gating behavior in TREK subfamily of the two-pore domain (K2P) Potassium channels.
a. (Supratim Ray) Calculus: functions, limits & continuity, differentiation/integration b. (K. Sekar) Linear Algebra: vectors, matrices, determinants, linear equations c. (Anand Srivastava) Statistics: elements of probability theory, discrete and continuous distributions, measures of central tendency, variability, confidence intervals, formulation of statistical hypotheses, tests of significance
Instructors: N. Srinivasan and Anand Srivastava (8-10 weeks)
2. MB206 (Aug 3:0): Conformational & structural aspects of biopolymer
Structure and conformation of biological molecules. Molecular scales driving forces behind higher order structural organization of proteins, lipids and nucleic acids
Instructors:Anand Srivastava (16 weeks)
3. MB 211 (January 3:1): Advance Sampling Methods in Biomolecular Simulations
Theoretical and computational aspects of various advance sampling and free energy calculation methods (maximum work theorem, Jarzinsky equality, umbrella sampling, replica exchange, metadynamics, markov state model, etc). Continuum representation of solvent and calculation of electrostatics and non-electrostatics component of solvation free energy. Method development and application of multiscale coarse graining methods such as force-matching, elastic network models, Inverse Boltzmann’s and relative entropy methods.
Molecular Biophysics Unit,
Indian Institute of Science,
Bangalore 560012, Karnataka, India
Email : email@example.com