INSTITUTO DE QUIMICA, FISICA DE LOS MATERIALES, MEDIOAMBIENTE Y ENERGIA
Unidad Ejecutora - UE
Ligand Uptake Modulation by Internal Water Molecules and Hydrophobic Cavities in Hemoglobins
J.P. BUSTAMANTE; S. ABBRUZZETTI; A. MARCELLI; D.F. GAUTO; L. BOECHI; A. BONAMORE; A. BOFFI; S. BRUNO; A. FEIS; P. FOGGI; C. VIAPPIANI; D.A. ESTRIN
JOURNAL OF PHYSICAL CHEMISTRY B
american chemical society
Lugar: Columbus; Año: 2014 vol. 118 p. 1234 - 1234
ABSTRACT: Internal water molecules play an active role in ligand uptakeregulation, since displacement of retained water molecules from proteinsurfaces or cavities by incoming ligands can promote favorable or disfavorableeﬀects over the global binding process. Detection of these water molecules byX-ray crystallography is diﬃcult given their positional disorder and lowoccupancy. In this work, we employ a combination of molecular dynamicssimulations and ligand rebinding over a broad time range to shed light into therole of water molecules in ligand migration and binding. Computationalstudies on the unliganded structure of the thermostable truncated hemoglobinfrom Thermobif ida f usca (Tf-trHbO) show that a water molecule is in the vicinity of the iron heme, stabilized by WG8 with theassistance of YCD1, exerting a steric hindrance for binding of an exogenous ligand. Mutation of WG8 to F results in asigniﬁcantly lower stabilization of this water molecule and in subtle dynamical structural changes that favor ligand binding, asobserved experimentally. Water is absent from the fully hydrophobic distal cavity of the triple mutant YB10F-YCD1F-WG8F(3F), due to the lack of residues capable of stabilizing it nearby the heme. In agreement with these eﬀects on the barriers forligand rebinding, over 97% of the photodissociated ligands are rebound within a few nanoseconds in the 3F mutant case. Ourresults demonstrate the speciﬁc involvement of water molecules in shaping the energetic barriers for ligand migration andbinding.