Protein–protein interactions: organization, cooperativity and mapping in a bottom-up Systems Biology approach

Abstract

Understanding and ultimately predicting protein associations is immensely important for functional genomics and drug design. Here, we propose that binding sites have preferred organizations. First, the hot spots cluster within densely packed 'hot regions'. Within these regions, they form networks of interactions. Thus, hot spots located within a hot region contribute cooperatively to the stability of the complex. However, the contributions of separate, independent hot regions are additive. Moreover, hot spots are often already pre-organized in the unbound (free) protein states. Describing a binding site through independent local hot regions has implications for binding site definition, design and parametrization for prediction. The compactness and cooperativity emphasize the similarity between binding and folding. This proposition is grounded in computation and experiment. It explains why summation of the interactions may over-estimate the stability of the complex. Furthermore, statistically, charge-charge coupling of the hot spots is disfavored. However, since within the highly packed regions the solvent is screened, the electrostatic contributions are strengthened. Thus, we propose a new description of protein binding sites: a site consists of (one or a few) self-contained cooperative regions. Since the residue hot spots are those conserved by evolution, proteins binding multiple partners at the same sites are expected to use all or some combination of these regions.

In silico analysis of detrimental mutations in ADD domain of chromatin remodeling protein ATRX that cause ATR-X syndrome: X-linked disorder

“…From this result, we confirmed that, out of 238 binding residues in all 17 mutant structures, 2 binding residues having identical flexibility, 39 binding residues having increased flexibility, and 197 binding residues having decreased flexibility. This result could clearly exemplified that decreased flexibility in the binding residues of 17 mutant structures of ADD domain changed the conformational state of interfacial residues and could affect the evolutionary molecular recognition of histone H3-peptide according to ''conformational selection'' method (Keskin et al 2005). Interestingly, two variants L192F and Q219P had more pronounced effect on ADD domain by computational tools (I-Mutant 2.0, SIFT, PolyPhen) and structure-based methods (total energy, RMSD, inter-intra molecular interactions, Rosetta energy score and normal mode analysis) leads to cause ATR-X syndrome.…”

Biophysics of Protein–Protein Interactions

“…All this will favour the establishment of strong enthalpic contributions, but these would not have a significant impact on the binding energetics if they were coupled to structuring effects in highly flexible regions of the protein. Interestingly, hot spots are generally well structured and preferably found in preexisting pockets in the free protein that are not affected by ligand induced conformational changes [161][162][163]. It could be argued that, among other factors, the high structural stability of these residues is, thus, determinant for their strong contribution to the binding energy.…”

Prism: Protein-Protein Interaction Prediction by Structural Matching

“…Identifying protein binding sites and knowing which proteins interact with which others are crucial for a better understanding of the bases of many biological processes. Despite the ongoing effort to decipher the complex nature of protein interactions, they are not still entirely understood (1)(2)(3)(4)(5). Protein binding sites have been thoroughly analyzed for the presence of certain physico-chemical and geometric properties that can be used to distinguish these regions from the non-interacting surface regions.…”