Abstract:

Ligands must displace water molecules from their corresponding protein surface binding site during association. Thus, protein binding sites are expected to be surrounded by non-tightly-bound, easily removable water molecules. In turn, the existence of packing defects at protein binding sites has been also established. At such structural motifs, named dehydrons, the protein backbone is exposed to the solvent since the intramolecular interactions are incompletely wrapped by non-polar groups. Hence, dehydrons are sticky since they depend on additional intermolecular wrapping in order to properly protect the structure from water attack. Thus, a picture of protein binding is emerging wherein binding sites should be both dehydrons rich and surrounded by easily removable water. In this work we shall indeed confirm such a link between structure and dynamics by showing the existence of a firm correlation between the degree of underwrapping of the protein chain and the mobility of the corresponding hydration water molecules. In other words, we shall show that protein packing defects promote their local dehydration, thus producing a region of “hot” interfacial water which might be easily removed by a ligand upon association.

Author affiliation: Sierra, Maria Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina.;

Author affiliation: Accordino, Sebastián Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina.;

Author affiliation: Rodríguez Fris, Jorge Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina.;

Author affiliation: Morini, Marcela Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina.;

Author affiliation: Appignanesi, Gustavo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina.;

Author affiliation: Fernandez, Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto Argentino de Matemáticas; Argentina; Institute for Advanced Study. Collegium Basilea; Suiza;