Structure and dynamics of α-MSH using DRISM integral equation theory and stochastic dynamics

The structural and dynamical features of the hormone α-MSH in solution have been examined over a 100 ns time scale by using free energy molecular mechanics models at room temperature. The free energy surface has been modeled using methods from integral equation theory and the dynamics by the Langevin equation. A modification of the accessible surface area friction drag model was used to calculate the atomic friction coefficients. The molecule shows a stable β-turn conformation in the message region and a close interaction between the side chains of His⁶, Phe⁷, and Trp⁹. A salt bridge between Glu⁵ and Arg⁸ was found not to be a preferred interaction, whereas a Glu⁵ and Lys¹¹ salt bridge was not sampled, presumably due to relatively high free energy barriers. The message region was more conformationally rigid than the N-terminal region. Several structural features observed here agree well with experimental results. The conformational features suggest a receptor-hormone interaction model where the hydrophobic side chains of Phe⁷ and Trp⁹ interact with the transmembrane portion of the MC1 receptor. Also, the positively charged side chain of Arg⁸ and the imidazole side chain of His⁶ may interact with the negatively charged portions of the receptor which may even be on the receptor's extracellular loops.