Ben Blackburne

Supervisor: Dr Jonathan Hirst

School: Chemistry, University of Nottingham

The course of protein evolution is determined by natural selection based on a function, which in turn is dependent on the three dimensional structure of the protein. If we wish to examine molecular evolution on a broad scale, we must consider these aspects over vast evolutionary landscapes. To do this we employ a "coarse-grained" or lattice protein model using a simplified folding code. Residues are reduced to a single point on a lattice, and assigned to be either hydrophobic or polar. We exhaustively search conformational space and sequence space, and find the set of sequences for a certain length that are able to fold to a thermodynamically stable ground state. Many proteins contain a binding pocket or active site, and this is an obvious focal point for examining fitness. If a ground state structure has an empty lattice site enclosed by the body of the protein, we consider the sequence to be functional, with the empty site as a binding pocket. We can characterise a fitness for the protein based on a simple model of non-specific hydrophobic binding.

This theoretical framework allows us to examine aspects of molecular evolution that experimental techniques are unable to address. Evolutionary landscapes can be determined exhaustively, and the path of molecular evolution determined through population dynamics simulations. In this way the effect of the constraints of structure, stability and function on the progress of evolution may be directly studied.

References:

J CHEM PHYS 119 (6): 3453-3460 AUG 8 2003
J CHEM PHYS 115 (4): 1935-1942 JUL 22 2001