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Add to Calendar 11/27/2017 3:00 pm 11/27/2017 4:00 pm America/Chicago Cooperative allosteric ligand binding in calmodulin DESCRIPTION:

Conformational dynamics is often essential for a protein’s function. For example, proteins areable to communicate the effect of binding at one site to a distal region of the molecule throughchanges 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. In this work, I focus on molecular dynamics simulations to understand microscopic origins ofligand binding cooperativity using a ubiquitous calcium-binding protein Calmodulin (CaM). Domain opening transitions of isolated domains of CaM in the absence of calcium shows that the simulated transition mechanism of nCaM follows a two-state behavior, while domain opening in cCaM involves global unfolding and refolding of the tertiary structure. The unfolded intermediate also appears in the landscape of nCaM, but at a higher temperature than it appears in cCaM’s energy landscape. I also investigate the structural origins of binding affinity and allosteric cooperativity of binding two calcium ions to each domain of CaM. I analyze the simulated binding curves within the framework of the classic Monod-Wyman-Changeux (MWC) model of allostery to extract the binding free energies to the closed and open ensembles. The analysis of the simulations offers a rationale for why the two domains differ in cooperativity: the higher cooperativity of cCaM is due to larger difference in affinity of its binding loops.Finally, I extend the work to investigate structural origins of binding cooperativity of four calcium ions to intact CaM. I focus on investigating the influence of this heterogeneity on the kinetic flux of binding pathways as a function of concentration. The formalism developed for Network Models of protein folding kinetics is used to evaluate the directed flux of all possible pathways between unligated and fully loaded CaM.

\n\nSPEAKER:

Dr. Prithviraj Nandigrami

Beckman Room 3269

false

Cooperative allosteric ligand binding in calmodulin

Speaker Dr. Prithviraj Nandigrami
Date: 11/27/2017
Time: 3 p.m. - 4 p.m.
Location:

Beckman Room 3269

Event Contact: Donna H Fackler
217-300-8022
dhfackler@ks.uiuc.edu
Cost:

NO Cost

Sponsor:

Theoretical and Computational Biophysics Group

Event Type: Seminar/Symposium
 

Conformational dynamics is often essential for a protein’s function. For example, proteins areable to communicate the effect of binding at one site to a distal region of the molecule throughchanges 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. In this work, I focus on molecular dynamics simulations to understand microscopic origins ofligand binding cooperativity using a ubiquitous calcium-binding protein Calmodulin (CaM). Domain opening transitions of isolated domains of CaM in the absence of calcium shows that the simulated transition mechanism of nCaM follows a two-state behavior, while domain opening in cCaM involves global unfolding and refolding of the tertiary structure. The unfolded intermediate also appears in the landscape of nCaM, but at a higher temperature than it appears in cCaM’s energy landscape. I also investigate the structural origins of binding affinity and allosteric cooperativity of binding two calcium ions to each domain of CaM. I analyze the simulated binding curves within the framework of the classic Monod-Wyman-Changeux (MWC) model of allostery to extract the binding free energies to the closed and open ensembles. The analysis of the simulations offers a rationale for why the two domains differ in cooperativity: the higher cooperativity of cCaM is due to larger difference in affinity of its binding loops.Finally, I extend the work to investigate structural origins of binding cooperativity of four calcium ions to intact CaM. I focus on investigating the influence of this heterogeneity on the kinetic flux of binding pathways as a function of concentration. The formalism developed for Network Models of protein folding kinetics is used to evaluate the directed flux of all possible pathways between unligated and fully loaded CaM.

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