Salt-bridge Networks within Globular and Disordered Proteins – Characterizing Trends for Designable Interactions

There has been fare amount of debate regarding the contribution of salt-bridges in the stabilization of protein folds. However, their participation in crucial protein functions are well established. The current study analyzes their modes of association, in terms of networks, both within globular proteins and also at protein-protein interfaces. Apart from the most common and trivial case of isolated salt-bridges, bifurcated salt-bridges appear to be a special salt-bridge motif both in terms of its topology and geometry and found ubiquitously in proteins and inter-protein complexes. Interesting and attractive examples presenting different interaction-modes have been highlighted. Bifurcated salt-bridges appear to function as molecular clips instrumental in stitching large surface contours of interacting protein-protein interfaces. The work also emphasizes the key role of salt-bridge mediated interactions in the partial folding of proteins containing large amount of disordered regions. Salt-bridge mediated interactions seem pivotal in promoting ‘disorder-to-order’ transitions for small disordered protein fragments and their stabilization upon binding. The results should guide to elucidate the modus operandi of these partially disordered proteins and also should be helpful to conceptualize how these proteins manage to keep necessary amount of disorder even in their functionally active bound forms, encouraging future studies. It should also be potentially beneficial towards the proposed notion of geometrically specific designable interactions involving salt-bridges.