Modeling of α‐MSH conformations with implicit solvent

Abstract

A conformational search for the most probable structures of the hormone alpha-MSH in aqueous solution was performed in order to help determine the structural features necessary for biological activity. The free-energy surface was modeled using methods from integral equation theory, and high-temperature molecular dynamics was used to enhance conformational sampling. Families of low free-energy structures have been found. The minimum energy structure shows a stable beta-turn conformation in the putative message region that is stabilized by a salt bridge between Glu5 and Lys11. The orientation of the side chains reflects the amphiphilic nature of the peptide, and a close interaction between the side chains of the His6, Phe7 and Trp9 was observed. Several structural features observed in the minimum energy structure agree well with experimental results. The conformational features led to a hypothesis of a receptor-hormone interaction model in which the hydrophobic side chains of Phe7 and Trp9 interact with the transmembrane portion of the human melanocortin (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.

Interactions of Human Melanocortin 4 Receptor with Nonpeptide and Peptide Agonists,

“…L265A mutation demonstrates a large effect only on the binding affinity and the potency of small-molecule agonists (Table 1) probably because the aliphatic side-chain of Leu 265 is more tightly packed with the cyclohexane ring of the peptidomimetics than with the corresponding planar ring of Trp 9 of the peptide. It can not be excluded, however, that D126A and H264A mutations may also impair plasma membrane targeting and/or assembly, as radiolabel binding and functional activation is dramatically reduced for these mutants.Our models are consistent with receptor-bound conformations of agonists that have been proposed previously (18,48,(56)(57)(58)(59). The best-fitting conformation of small agonist, THIQ was similar to the crystal structure of this molecule (see Results).…”

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

“…This is not surprising since peptide bond dihedral angles, except those involving proline, are expected to be in the trans conformation. However, the most favorable structure that we observed in a previous study 66 did have a cis peptide bond at Pro 12 , which may have been instrumental in bringing the hydrophobic side chain of Val 13 in close proximity to the hydrophobic aromatic rings of Phe 7 and Trp 9 . There have been no experimental reports or theoretical re- ports of a cis peptide bond on proline, although this has been observed in studies of other peptides.…”

“…In some studies models of both linear analogues containing D-Phe 7 and superpotent cyclic analogues are consistent with a His 6 -Trp 9 turn. 1,35,44,55 However, in other studies of superpotent linear and cyclic analogues, 47,56,66 the C ␣ of His 6 and of Trp 9 seem too distant in reported active conformations to be consistent with a His 6 -Trp 9 turn. Similarly, in our earlier work 64 we had found a ␤-turn may also exist at Phe 7 -Gly 10 .…”

“…32 The generally extended nature of the peptide is also reflected in the end-to-end distance of the peptide, which is over 25 Å (Figure 5a) and in the relatively large separation between the aromatic side chains of Tyr 2 and Trp 9 , which were more than 15 Å apart (Figure 6b). Results from experimental studies 90,91 and our previous computational work 66 suggested that this distance can have a population less than 10 Å.…”

“…Recently 66 we have performed a thorough search on the conformational space of ␣-MSH. We incorporated the effect of aqueous solvent in our model by using methods based on integral equation methods of statistical mechanics.…”