White Rose University Consortium logo
University of Leeds logo University of Sheffield logo York University logo

Coarse-grained models of biomolecule dynamics and allostery

Toncrova, Hedvika (2010) Coarse-grained models of biomolecule dynamics and allostery. PhD thesis, University of Leeds.

Available under License Creative Commons Attribution-Noncommercial-Share Alike 2.0 UK: England & Wales.

Download (31Mb)


Recently, it has become increasingly accepted that thermal fluctuations take active part in functional tasks of biological molecules. We employ a set of coarse-grained models to investigate the mechanism of transmission of allosteric signal via spatial fluctuations. Our models are coarser than those in computational techniques established in molecular biology, but allow for both the identification of candidates for the essential physical structures and also the analytical determination of thermodynamic quantities that define ligand binding. The models are constructed for general classes of macromolecules and are validated through parameterisation from experiments and atomistic simulations. In the first part of this thesis we investigate the “dynamic allostery” in dimeric proteins composed of two identical subunits. We demonstrate that cooperative effects upon binding of two identical ligands can arise purely through modification of slow global vibrational modes of the protein. We parameterise the model on a test case, the CAP homodimer. Finally, we explain the role of local, fast vibrations in the allosteric effect and propose a general protocol for interpreting thermodynamic parameters of dynamically allosteric homodimers. The second part of this thesis considers allosteric effects in DNA, an example of nearly uniform elastic medium. The DNA is modeled as an elastic rod and substrate binding as local increase of its bending and twisting rigidity. This results in altered structure of normal modes and leads to qualitatively different type of dynamic allostery compared to that of the discrete models previously employed to study allosteric effects in proteins. Dynamic allostery in DNA is found always to be negative, due to an anti-correlated amplitude of thermal fluctuations at the binding site and around it. This allows us to draw conclusions about general design rules of allosteric molecules and highlight the controlling feature that biological molecules evolved to optimize their dynamics for their function.

Item Type: Thesis (PhD)
ISBN: 978-0-85731-065-1
Academic Units: The University of Leeds > Faculty of Maths and Physical Sciences (Leeds) > School of Physics and Astronomy (Leeds)
Identification Number/EthosID: uk.bl.ethos.530618
Depositing User: Ethos Import
Date Deposited: 31 Mar 2011 12:30
Last Modified: 07 Mar 2014 11:23
URI: http://etheses.whiterose.ac.uk/id/eprint/1441

You do not need to contact us to get a copy of this thesis. Please use the 'Download' link(s) above to get a copy.
You can contact us about this thesis. If you need to make a general enquiry, please see the Contact us page.

Actions (repository staff only: login required)