title   
  

Subtle pH differences trigger single residue motions for moderating conformations of calmodulin

Atılgan, Ali Rana and Aykut, Ayşe Özlem and Atılgan, Canan (2011) Subtle pH differences trigger single residue motions for moderating conformations of calmodulin. Journal of Chemical Physics, 135 (15). ISSN 0021-9606

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Official URL: http://dx.doi.org/10.1063/1.3651807

Abstract

This study reveals the essence of ligand recognition mechanisms by which calmodulin (CaM) controls a variety of Ca2+ signaling processes. We study eight forms of calcium-loaded CaM each with distinct conformational states. Reducing the structure to two degrees of freedom conveniently describes main features of the conformational changes of CaM via simultaneous twist-bend motions of the two lobes. We utilize perturbation-response scanning (PRS) technique, coupled with molecular dynamics simulations. PRS is based on linear response theory, comprising sequential application of directed forces on selected residues followed by recording the resulting protein coordinates. We analyze directional preferences of the perturbations and resulting conformational changes. Manipulation of a single residue reproduces the structural change more effectively than that of single/pairs/triplets of collective modes of motion. Our findings also give information on how the flexible linker acts as a transducer of binding information to distant parts of the protein. Furthermore, by perturbing residue E31 located in one of the EF hand motifs in a specific direction, it is possible to induce conformational change relevant to five target structures. Independently, using four different pKa calculation strategies, we find this particular residue to be the charged residue (out of a total of 52), whose ionization state is most sensitive to subtle pH variations in the physiological range. It is plausible that at relatively low pH, CaM structure is less flexible. By gaining charged states at specific sites at a pH value around 7, such as E31 found in the present study, local conformational changes in the protein will lead to shifts in the energy landscape, paving the way to other conformational states. These findings are in accordance with Fluorescence Resonance Energy Transfer (FRET) measured shifts in conformational distributions towards more compact forms with decreased pH. They also corroborate mutational studies and proteolysis results which point to the significant role of E31 in CaM dynamics.

Item Type:Article
Additional Information:Article Number: 155102
Uncontrolled Keywords:biochemistry; molecular biophysics; molecular configurations; molecular dynamics method; pH; proteins
Subjects:Q Science > Q Science (General)
ID Code:17686
Deposited By:Canan Atılgan
Deposited On:03 Jan 2012 11:29
Last Modified:03 Jan 2012 11:29

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