Background

Proteins are molecular machines with complex mechanisms that are in general poorly understood.  One of the main techniques used to gain detailed knowledge of how proteins function is computer simulation.  The project will use simulation methods to investigate an intriguing, but little understood, feature in the working of some proteins.

Many proteins are constructed from domains and move between an open and closed domain conformation.

This project is based on a number of studies that suggest a domain-lock mechanism operates in some enzymes (see references (i),(ii) and (iii)), keeping them in an open conformation until unlocked by a functional ligand.    

The project has relevance to structure-based computer-aided drug design, employed by large pharmaceutical companies, where the accurate modelling of protein conformational change is crucial (see reference iv) but often neglected due to gaps in our understanding.

Aims and Objectives of Project and scientific training

The aim is to understand the workings of the lock mechanism in proteins that have been the focus of our research over the years. This computational project will require the student to apply a wide-range of computational techniques including Molecular Dynamics simulation (e.g. AMBER, Gromacs), inverse-kinematics, and bioinformatics.

The student will benefit by joining a small group of three other PhD students who are working on related projects.

It is envisaged that the student will spend some time in the group of Dr Roccatano (Jacobs University Bremen, Germany) and also spend some time in Tokyo working in the groups of Professor Akio Kitao at the University of Tokyo and also with Professor Kei Yura at Ochanomizu University.  To support the latter visit a Japan Society for the Promotion of Science Summer Programme fellowship will be applied for.  This programme supports students at the PhD level and will offer the student a unique opportunity to expand their expert knowledge in the area of biomolecular modelling in two of Japan's top groups in this area.

S.Hayward, A. Kitao, "Molecular dynamics simulations of NAD+-induced domain closure in horse liver alcohol dehydrogenase", Biophysical Journal, 91: 1823-1831, 2006

D.Roccatano, A.E.Mark, S.Hayward, "Investigation of the Mechanism of Domain Closure in Citrate Synthase by Molecular Dynamics Simulation", Journal of Molecular Biology, 301, 1039, 2001

S.Hayward, A.Kitao, "Effect of end constraints on protein loop kinematics", Biophysical Journal, 98(9), 1976-1985, 2010

SJ Teague, "Implications of protein flexibility for drug discovery", Nature Reviews, 527:527-541, 2003