arXiv subjects

Prithviraj Nandigrami

Publications and source records attributed to Prithviraj Nandigrami.

3 recordsLinked to original sources

arXiv2016

Gradient-driven diffusion and pattern formation in crowded mixtures

Gradient-driven diffusion in crowded, multicomponent mixtures is a topic of high interest because of its role in biological processes such as transport in cell membranes. In partially phase-separated solutions, gradient-driven diffusion affects microstructure, which in turn affects diffusivity; a key question is how this complex coupling controls both transport and pattern formation. To examine these mechanisms, we study a two-dimensional multi-component lattice gas model, where "tracer" molecules diffuse between a source and a sink separated by a solution of sticky "crowder" molecules that cluster to form dynamically evolving obstacles. In the high temperature limit, crowders and tracers are miscible and transport may be predicted analytically. At intermediate temperatures, crowders phase separate into clusters that drift toward the tracer sink. As a result, steady-state tracer diffusivity depends non-monotonically on both temperature and crowder density and we observe a variety of complex microstructures. In the low temperature limit, crowders rapidly aggregate to form obstacles that are kinetically arrested; if crowder density is near the percolation threshold, resulting tracer diffusivity shows scaling behavior with the same scaling exponent as the random resistor network model. Though highly idealized, this simple model reveals fundamental mechanisms governing coupled gradient-driven diffusion, phase separation, and microstructural evolution in crowded solutions.

cond-mat.soft↗

arXiv2016

Coarse-grained molecular simulations of allosteric cooperativity

Interactions between a protein and a ligand are often accompanied by a redistribution of the population of thermally accessible conformations. This dynamic response of the protein's functional energy landscape enables a protein to modulate binding affinities and control binding sensitivity to ligand concentration. In this paper, we investigate the structural origins of binding affinity and allosteric cooperativity of binding two calcium ions to each domain of calmodulin (CaM) through simulations of a simple coarse-grained model. In this model, the protein's conformational transitions between open and closed conformational ensembles are simulated explicitly and ligand binding and unbinding is treated implicitly within the Grand Canonical Ensemble. Ligand binding is cooperative because the binding sites are coupled through a shift in the dominant conformational ensemble upon binding. The classic Monod-Wyman-Changeux model of allostery with appropriate binding free energy to the open and closed ensembles accurately describes the simulated binding thermodynamics. The simulations predict that the two domains of CaM have distinct binding affinity and cooperativity. In particular, C-terminal domain binds calcium with higher affinity and greater cooperativity than the N-terminal domain. From a structural point of view, the affinity of an individual binding loop depends sensitively on the loop's structural compatibility with the ligand in the bound ensemble, as well as the conformational flexibility of the binding site in the unbound ensemble.

physics.bio-ph↗

arXiv2016

Comparing allosteric transitions in the domains of calmodulin through coarse-grained simulations

Calmodulin (CaM) is a ubiquitous calcium binding protein consisting of two structurally similar domains with distinct stabilities, binding affinities, and flexibilities. We present coarse grained simulations that suggest the mechanism for the domain's allosteric transitions between the open and closed conformations depend on subtle differences in the folded state topology of the two domains. Throughout a wide temperature range, the simulated transition mechanism of the N-terminal domain (nCaM) follows a two-state transition mechanism while domain opening in the C-terminal domain (cCaM) involves unfolding and refolding of the tertiary structure. The appearance of the unfolded intermediate occurs at a higher temperature in nCaM than it does in cCaM consistent with nCaM's higher thermal stability. Under approximate physiological conditions, the simulated unfolded state population of cCaM accounts for 10% of the population with nearly all of the sampled transitions (approximately 95%) unfolding and refolding during the conformational change. Transient unfolding significantly slows the domain opening and closing rates of cCaM. This potentially influences the mechanism of calcium binding to each domain.

physics.bio-ph↗