Interplay between protein recognition specificity and promiscuity Despite their great specificity and robustness, proteins exhibit a remarkable adaptability and plasticity (promiscuity). Recent experiments suggest that proteins may promiscuously interact with ligands and substrates other than those they are designed for. We are interested in understanding the interplay between protein recognition specificity and promiscuity. The key question is how a protein can be both specific and promiscuous? What are the sequence and structural characteristics of protein interfaces that provide multi-specificity? One of our key objectives is to elucidate the limits on the selectivity of multi-specific binding imposed by biophysical properties of protein interfaces. What is the connection between microscopic organization of protein interfaces and their systems-level, network interaction properties? What is the effect of protein conformational flexibility on protein multi-specificity? Do flexible elements of protein structure increase or reduce protein specificity? What is the effect of sequence correlations on protein-protein recognition specificity? These are the key questions that we ask. Design principles of intrinsically disordered proteins Numerous proteins remain unfolded under physiological conditions. Such proteins are termed ‘intrinsically disordered’ proteins (IDPs). They are also termed ‘natively unfolded’, ‘intrinsically unstructured’, and ‘natively disordered’. Bioinformatics methods have been used to predict the degree of disorder in many whole proteomes, containing tens of thousands proteins. This analysis predicts that the disorder is very strong in eukaryotes, and it is much weaker in archaea and bacteria. In particular it is predicted that in higher eukaryotes, 75% of their signaling proteins contain long disordered regions, about 50% of their total proteins contain such long disordered regions, and 25% of their proteins are predicted to be fully disordered. These striking numbers suggest that understanding design principles leading to protein disorder is as important as understanding principles of protein folding. We are interested in understanding the effect of protein sequence correlations on protein foldability.

Interplay between protein recognition specificity and promiscuity

Despite their great specificity and robustness, proteins exhibit a remarkable adaptability and plasticity (promiscuity). Recent experiments suggest that proteins may promiscuously interact with ligands and substrates other than those they are designed for. We are interested in understanding the interplay between protein recognition specificity and promiscuity.

The key question is how a protein can be both specific and promiscuous? What are the sequence and structural characteristics of protein interfaces that provide multi-specificity? One of our key objectives is to elucidate the limits on the selectivity of multi-specific binding imposed by biophysical properties of protein interfaces. What is the connection between microscopic organization of protein interfaces and their systems-level, network interaction properties? What is the effect of protein conformational flexibility on protein multi-specificity? Do flexible elements of protein structure increase or reduce protein specificity? What is the effect of sequence correlations on protein-protein recognition specificity? These are the key questions that we ask.

Design principles of intrinsically disordered proteins

Numerous proteins remain unfolded under physiological conditions. Such proteins are termed ‘intrinsically disordered’ proteins (IDPs). They are also termed ‘natively unfolded’, ‘intrinsically unstructured’, and ‘natively disordered’. Bioinformatics methods have been used to predict the degree of disorder in many whole proteomes, containing tens of thousands proteins. This analysis predicts that the disorder is very strong in eukaryotes, and it is much weaker in archaea and bacteria. In particular it is predicted that in higher eukaryotes, 75% of their signaling proteins contain long disordered regions, about 50% of their total proteins contain such long disordered regions, and 25% of their proteins are predicted to be fully disordered. These striking numbers suggest that understanding design principles leading to protein disorder is as important as understanding principles of protein folding.We are interested in understanding the effect of protein sequence correlations on protein foldability.