Comparison of Generalised Born/Surface Area with Periodic Boundary Simulations to Study Protein Unfolding

Abstract

Simulations comparing the rapid unfolding behaviour of the model protein barnase under explicit and implicit solvent systems have been undertaken in order to validate a faster implicit solvent method for studying proteins which are kinetically stable  in silico. A comparison is made between all-atom explicitly solvated simulations of barnase undertaken using Particle Mesh Ewald electrostatic interactions with all-atom implicit solvent simulations undertaken using the generalised born/surface area (GBSA) method with a long non-bonded cut-off. The two explicit solvent unfolding trajectories appear to explore slightly different pathways showing the importance of having statistically valid ensembles which are not accessible from a single trajectory. The 500 K GBSA trajectory is unsuitable  for exploring intermediate structures on the unfolding pathway of barnase, as the protein almost immediately jumps to a predominately random coil conformation. However, dropping the temperature to 400 K gives rise to trajectories where the protein is unable to climb out of the energy well containing the first intermediate state, in a reasonable timescale. A similar pattern to the explicit solvent unfolding trajectories is seen in 450 K GBSA runs, with the intermediate states differing between trajectories. The development of computer simulation methods suitable  for application to more kinetically stable  proteins will offer insight into the atomic detail of the conformational changes associated with protein unfolding diseases.

Keywords:

• Barnase
• Generalised born/surface area
• Protein molecular dynamics simulation
• Protein unfolding

Acknowledgements

We would like to thank Drs Dave Houldershaw and Richard Westlake for computation support. We acknowledge the BBSRC for funding the Beowulf cluster. C. Slingsby and A.G. Purkiss are grateful for the financial support of the Medical Research Council, and J.T. Macdonald for a Medical Research Council studentship.