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Toward the Understanding of MNEI Sweetness from Hydration Map Surfaces

Alfonso De Simone ^* , Roberta Spadaccini , Piero A. Temussi ^*  ¶ and Franca Fraternali ^* ||

^* National Institute for Medical Research, NW7 1AA London, United Kingdom; Dipartimento delle Scienze Biologiche Sezione Biostrutture and CNISM, Università di Napoli Federico II, Naples, Italy; EMBL, Heidelberg, Germany; Dipartimento di Chimica, Università di Napoli Federico II, Complesso Universitario Monte Sant'Angelo, 80126 Naples, Italy; ^¶ Centro Linceo "Beniamino Segre", Accademia dei Lincei, Rome, Italy; and ^|| The Randall Centre for Molecular Mechanisms of Cell Function, King's College London, London SE1 1UL, United Kingdom

Correspondence: Address reprint requests to Franca Fraternali, E-mail: temussi{at}unina.it, or ffranca{at}nimr.mrc.ac.uk.

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.

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