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1. Nandigrami, Prithviraj. Cooperative allosteric ligand binding in calmodulin.

Degree: PhD, College of Arts and Sciences / Department of Physics, 2017, Kent State University

Conformational dynamics is often essential for a protein's function. For example, proteins are able to communicate the effect of binding at one site to a distal region of the molecule through changes in its conformational dynamics. This so called allosteric coupling fine tunes the sensitivity of ligand binding to changes in concentration. A conformational change between a "closed" (apo) and an "open" (holo) conformation upon ligation often produces this coupling between binding sites. Enhanced sensitivity between the unbound and bound ensembles leads to a sharper binding curve. There are two basic conceptual frameworks that guide our visualization about ligand binding mechanisms. First, a ligand can stabilize the unstable "open" state from a dynamic ensemble of conformations within the unbound basin. This binding mechanism is called conformational selection. Second, a ligand can weakly bind to the low-affinity "closed" state followed by a conformational transition to the "open" state. This is called induced fit binding.In this dissertation, I focus on molecular dynamics simulations to understand microscopic origins of ligand binding cooperativity. A minimal model of allosteric binding transitions must include ligand binding/unbinding events, while capturing the transition mechanism between two distinct meta-stable free energy basins. Due in part to computational timescales limitations, work in this dissertation describes large-scale conformational transitions through a simplified, coarse-grained model based on the energy basins defined by the open and closed conformations of the protein Calmodulin (CaM). CaM is a ubiquitous calcium-binding protein consisting of two structurally similar globular domains connected by a flexible linker. The two domains of CaM, N-terminal domain (nCaM) and C-terminal domain (cCaM) consists of two helix-loop-helix motifs (the EF-hands) connected by a flexible linker. Each domain of CaM consists of two binding loops and binds 2 calcium ions each. The intact domain binds up to 4 calcium ions. The simulations use a coupled molecular dynamics/monte carlo scheme where the protein dynamics is simulated explicitly, while ligand binding/unbinding are treated implicitly. This helps us characterize complementary thermodynamic and kinetic description of calcium binding mechanism to CaM.In the model, ligand binding/unbinding events coupled with a conformational change of the protein within the grand canonical ensemble. Here, ligand concentration is controlled through the chemical potential (µ). This allows us to use a simple thermodynamic model to analyze the simulated data and quantify binding cooperativity. Simulated binding titration curves are calculated through equilibrium simulations at different values of µ.First, I study domain opening transitions of isolated nCaM and cCaM in the absence of calcium. This work is motivated by results from a recent analytic variational model that predicts distinct domain opening transition mechanism for the domains of CaM. This is a surprising result because… Advisors/Committee Members: Portman, John (Advisor).

Subjects/Keywords: Physics; Biophysics; Protein; Ligand; Free Energy; Conformational Dynamics; Allostery; Cooperativity

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APA (6th Edition):

Nandigrami, P. (2017). Cooperative allosteric ligand binding in calmodulin. (Doctoral Dissertation). Kent State University. Retrieved from

Chicago Manual of Style (16th Edition):

Nandigrami, Prithviraj. “Cooperative allosteric ligand binding in calmodulin.” 2017. Doctoral Dissertation, Kent State University. Accessed July 20, 2018.

MLA Handbook (7th Edition):

Nandigrami, Prithviraj. “Cooperative allosteric ligand binding in calmodulin.” 2017. Web. 20 Jul 2018.


Nandigrami P. Cooperative allosteric ligand binding in calmodulin. [Internet] [Doctoral dissertation]. Kent State University; 2017. [cited 2018 Jul 20]. Available from:

Council of Science Editors:

Nandigrami P. Cooperative allosteric ligand binding in calmodulin. [Doctoral Dissertation]. Kent State University; 2017. Available from: