Towards an understanding of the mechanical stability and energy landscape of proteins: An approach based on Molecular Dynamics simulations. (360G-Wellcome-080708_Z_06_Z)

£130,015

Towards an understanding of the mechanical stability and energy landscape of proteins: An approach based on Molecular Dynamics simulations The properties of proteins or their complexes are often characterised in terms of their thermodynamic stability and yet it is becoming clear that many biological processes are in fact mechanically mediated. Examples include protein degradation, the transport of proteins across membranes, and the roles of Titin and Filamin in muscle contraction and the cross-linking of cortical Actin networks respectively. In addition, experimental data is now emerging which suggests that certain protein mutations leading to disease are correlated to the mechanical stability of the proteins in question. For instance, certain developmental diseases have been linked to mutations in Filamin and are postulated to be due to compromised cell motility and/or membrane stability. Even where mechanical properties are not directly biologically relevant, such studies provide clean, single molecule information about the underlying energy landscape. Despite the extensive amount of work that has been performed in the last decade or so, a number of fundamental issues still remain unresolved. Thus, the over-riding aim of this project is to provide insight and clarification to some of the important issues and to make more effective use of single molecule pulling experiments where Leeds is an acknowledged world leader. Specifically, the objectives are the following: 1. To determine which atomistic models used in molecular dynamics simulations are the most adequate in reproducing mechanical unfolding experiments. 2. To elucidate the molecular determinants of mechanical strength in proteins; for example, the roles and relative importance of backbone hydrogen bonding, side-chains, and water. 3. To establish the relationship between mechanical properties and other biophysical parameters (e.g. native state fluctuations or thermal unfolding pathways). 4. To establish the relationship between the mechanical properties of proteins (with and without mechanical function) and sequence conservation data. Certainly, a better understanding of these issues will also contribute to understanding of the folding and function of proteins in general.

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Grant Details

Amount Awarded 130015
Applicant Surname Yew
Approval Committee Molecules, Genes and Cells Funding Committee
Award Date 2006-05-22T00:00:00+00:00
Financial Year 2005/06
Grant Programme: Title PhD Studentship (Basic)
Internal ID 080708/Z/06/Z
Lead Applicant Mr Zu Yew
Partnership Value 130015
Planned Dates: End Date 2010-09-30T00:00:00+00:00
Planned Dates: Start Date 2006-10-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Yorkshire and the Humber
Sponsor(s) Prof Alan Berry