Energetic determinants of protein binding specificity: Insights into protein interaction networks

Abstract

One of the challenges of the postgenomic era is to provide a more realistic representation of cellular processes by combining a systems biology description of functional networks with information on their interacting components. Here we carried out a systematic large-scale computational study on a structural protein-protein interaction network dataset in order to dissect thermodynamic characteristics of binding determining the interplay between protein affinity and specificity. As expected, interactions involving specific binding sites display higher affinities than those of promiscuous binding sites. Next, in order to investigate a possible role of modular distribution of hot spots in binding specificity, we divided binding sites into modules previously shown to be energetically independent. In general, hot spots that interact with different partners are located in different modules. We further observed that common hot spots tend to interact with partners exhibiting common binding motifs, whereas different hot spots tend to interact with partners with different motifs. Thus, energetic properties of binding sites provide insights into the way proteins modulate interactions with different partners. Knowledge of those factors playing a role in protein specificity is important for understanding how proteins acquire additional partners during evolution. It should also be useful in drug design.

Topology of protein interaction network shapes protein abundances and strengths of their functional and nonspecific interactions

“…This "frustration" between functional and nonfunctional interactions is resolved by limiting effective concentrations of stable pairs and date triangles in our model cells and weakening of their functional PPIs. Recent computational analysis of PPI energetics confirmed this prediction by demonstrating that proteins that have more functional partners in the PPI network have weaker functional interactions (22). An interesting possibility to overcome this frustration effect is to keep sequences of some proteins, which have multiple interaction partners, hydrophilic by making these proteins intrinsically disordered as has been indeed observed (23).…”

Structural and physico-chemical effects of disease and non-disease nsSNPs on proteins

“…Besides binding affinity, the binding specificity is also important to consider in regards to protein interactions. Taking into consideration the large number of different macromolecules in living cells, binding specificity plays an important role in recognizing unambiguous binding partners among an overabundance of other molecules [41, 42]. Binding specificity includes multiple factors such as concentrations and compartmentalization of the macromolecules, their shapes, charge and steric complementarity, conformational flexibility, the ability to recognize each other at relatively large distance (mainly through non-specific electrostatic interactions) and to form functioning complex by specific interactions within hot spots [41, 43].…”

Identification and regulation of the catalytic promiscuity of (−)-γ-lactamase from Microbacterium hydrocarbonoxydans

“…The identification of promiscuous activities is recognized as a necessary but difficult task, although some progress has been made in this field (Carbonell et al 2009;Gomez et al 2003). To this end, global structural similarity searches can provide some clues about protein functions and greatly narrow the range of possible enzyme candidates; the number of time and cost-consuming experimental validations could also be reduced via this strategy.…”