Are Hot-Spots Occluded from Water?

Protein-protein interactions are the basis of many biological processes and are governed by focused regions with high binding affinities, the hot-spots (HS).(Martins et al., 2013, Moreira, Martins, et al., 2012) It was proposed that these regions are surrounded by areas with higher packing density leading to solvent exclusion around them - “the O-ring theory”.(Bogan & Thorn, 1998) This important inference still lacks sufficient demonstration. We have used Molecular Dynamics (MD) simulations to investigate the validity of the O-ring theory in the context of the conformational flexibility of the proteins, which is critical for function in general and for interaction with water, in particular. For a database of 160 residues in 9 complexes the MD results were analyzed for a variety of solvent accessible surface area features, radial distribution functions, protein-water distances and water residence times. The measurement of the average Solvent Accessible Surface Area features for the HS and null-spots (NS), as well as data for corresponding radial distribution functions, identify distinct properties for these two sets of residues. HS are found to be occluded from the solvent. This study provides strong evidence in support of the O-ring theory.(Moreira, Ramos, et al., 2012)Bogan, A. A. & Thorn, K. S. (1998). Journal of Molecular Biology 280, 1-9.Martins, J., Ramos, R. & Moreira, I. (2013). Communications in computational physics 13, 238-255.Moreira, I. S., Martins, J. M., Ramos, M. J., Fernandes, P. A. & Ramos, M. J. (2012). Biochem. Biophys. Acta, Available online.Moreira, I. S., Ramos, R. M., Martins, J. M., Fernandes, P. A. & Ramos, M. J. (2012). In submission.