title: Toward the understanding of MNEI sweetness from hydration map surfaces.
abstract: The binding mechanism of sweet proteins to their receptor, a G-protein-coupled receptor, is not supported by direct structural information. In principle, the key groups responsible for biological activity (glucophores) can be localized on a small structural unit (sweet finger) or spread on a larger surface area. A recently proposed model, called "wedge model", implies a large surface of interaction with the receptor. To explore this model in greater detail, it is necessary to examine the physicochemical features of the surfaces of sweet proteins, since their interaction with the receptor, with respect to that of small sweeteners, is more dependent on general physicochemical properties of the interface, such as electrostatic potential and hydration. In this study, we performed exhaustive molecular dynamics simulations in explicit water of the sweet protein MNEI and of its structural mutant G-16A, whose sweetness is one order of magnitude lower than that of MNEI. Solvent density and self-diffusion calculated from molecular dynamics simulations suggest a likely area of interaction delimited by four stretches arranged as a tetrahedron whose shape is complementary to that of a cavity on the surface of the receptor, in agreement with the wedge model. The suggested area of interaction is amazingly consistent with known mutagenesis data. In addition, the asymmetric hydration of the only helix in both proteins hints at a specific role for this secondary structure element in orienting the protein during the binding process.
authors.affiliation: National Institute for Medical Research, NW7 1AA London, United Kingdom.
authors.forename: Alfonso
authors.initials: A
authors.lastname: De Simone
authors.forename: Roberta
authors.initials: R
authors.lastname: Spadaccini
authors.forename: Piero A
authors.initials: PA
authors.lastname: Temussi
authors.forename: Franca
authors.initials: F
authors.lastname: Fraternali
mesh_terms: D003198:Computer Simulation; D008958:Models, Molecular; D010449:Peptide Mapping; D010940:Plant Proteins / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*; D013549:Sweetening Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D010940:Plant Proteins; D043562:Receptors, G-Protein-Coupled; D013549:Sweetening Agents; C002541:monellin protein, Dioscoreophyllum cumminsii; C431926:taste receptors, type 1