Comparisons of the conformational biases imposed bytrans-2,3-methanomethionine and α-methylmethionine

Abstract

A comparative study of four peptidomimetics of the sequence Phe‐Met‐Arg‐Phe‐amide (FMRFa) was performed to compare the conformational bias caused by trans‐2,3‐methanomethionine and α‐methylmethionine stereoisomers. The specific compounds studied were F[(2S,3S)‐cyclo‐M] RFa, F[(2R,3R)‐cyclo‐M]RFa, F[(S)‐α‐MeM]RFa, and F[(R)‐α‐MeM]RFa. Molecular simulations based on CHARMm 22 indicate that γ‐turn, inverse γ‐turn, and α‐helical conformations about the cyclo‐M residue are accessible to the two F[cyclo‐M]RFa stereoisomers. Similar calculations for F[(S)‐α‐MeM]RFa, and F[(R)‐α‐MeM]RFa indicate that the α‐methylamino acids tend to favor α‐helical conformations. The nmr data is presented for the four peptidomimetics. Most informative were the rotating frame nuclear Overhauser effect cross peaks between the NH protons proximal to the methionine surrogates, and the Cβ hydrogens. Overall, these nmr data indicate F[(2S,3S)‐cyclo‐M]RFa and F[(2R,3R)‐cyclo‐M]RFa preferentially adopt inverse γ‐turn and γ‐turn conformations, respectively, whereas F[(S)‐α‐MeM]RFa and F[(R)‐α‐MeM]RFa tend to form partial left‐ and right‐handed helical structures (although energy differences between the two turn structures, and between the two helical structures are likely to be small). It is suggested that the wider NH‐Cα‐CO angle of cyclopropane amino acids and their more severe steric requirements around the Cβ carbons force the peptidomimetic N‐ and C‐termini into the same region of conformational space. This favors C7 turns in the cyclopropane amino acid series relative to the less constrained α‐methyl derivatives. © 1997 John Wiley & Sons, Inc. Biopoly 42: 439–453, 1997

Control of peptide conformation by the Thorpe-Ingold effect (C?-tetrasubstitution)

“…Following the pioneering work of Stammer and co‐workers,196–200 an impressive set of papers was recently emanated on the 3D structural preferences of side‐chain substituted, diastereomeric Ac 3 c201–216 and Ac 6 c217–220 residues (Figure 12). From these investigations it is evident that the structural bias toward folded conformations exhibited by the two unsubstituted cycloalkyl residues is in general preserved by their side‐chain derivatives.…”

Conformational Preferences of RNase A C-Peptide Derivatives Containing a Highly Constrained Analogue of Phenylalanine

“…With respect to the first goal, RN-24 is significantly different from other model systems that have been used. [30][31][32][33][34][35][36] This is important because there is no ideal system for studying conformational biases of cyclopropane amino acids, so conclusions must be drawn from several different systems. Short linear peptides (e.g., 3-5 residues) yield useful data, but interpretation is complicated by ill-defined, random-coil conformational states that are hard to identify, even after substitution with a restricted amino acid.…”

Rapid synthesis of cyclopropane-dipeptide analogues

“…Such compounds, as well as their synthetic counterparts, have been shown to be either particularly valuable tools for the determination of structure-activity relationships [5][6][7][8][9][10][11] or they are good enzyme inhibitors [12][13][14], some having even promising therapeutic effects in humans [15]. As a consequence, there is a special need to design synthetic methods that can quickly provide cyclopropane(-substituted) peptides (or analogues) for evaluation as biological tools or enzyme inhibitors.…”