Paramagnetic perturbation profiles of protein surface accessibility and hydration

Targeting protein-protein interactions for a therapeutic purpose is an attractive idea that has proved to be extremely challenging in practice. This is due to the large and flat landscape of most contact surfaces that make them less amenable to intervention by a small molecule. However, in recent years a growing body of evidence has demonstrated that small molecules can disrupt such large and complex protein interactions by binding to interface “hotspots” with drug-like potencies (1). The fact that small molecules bind targeted proteins in surface pockets which are not present in protein-protein interfaces indicates that conventional drug design procedures, based on the available structural information, are not suitable to discover molecules which can interfere with the protein-protein interaction process. Thus, we are developing criteria and algorithms to search for transient pockets on the protein surface which can accommodate molecules disrupting protein-protein adducts. Molecular Dynamics simulations, rather than static molecular structures, are used as a rational basis for Dynamic Drug Design. Protein-protein interactions involving chemokines are of primary relevance, as the immune system relies on chemokine signaling to direct lymphocyte homing, orchestrate inflammatory responses, and stimulate wound healing. Outside of these normal functions, chemokines and their receptors also participate in numerous disease states, including HIV/AIDS, asthma, autoimmune diseases, and cancer. We have investigated the transient pocket formation on the surface of SDF1-α, the chemokine stromal cell-derived factor 1, a structurally resolved protein (2) which directs stem cell homing and breast cancer metastasis. The already established acceptor capability of hydrogen bonds exhibited by TEMPOL towards free backbone amides (3) is proposed as an experimental filter to identify surface hotspots among all the predicted transient pockets.