The conformational influences of (2S,3S)-2,3-methanomethionine ((2S,3S)-cyclo-Met or (2S,3S)-cyclo-M) were studied to ascertain possible effects of substituting such constrained amino acids into small peptides. The peptide chosen for study was the anti-opiate Phe-Met-Arg-Phe-NH2 (FMRF-NH2 using the one-letter code). Consequently, FMRF-NH2 and F((2S,3S)-cyclo-M)RF-NH2 were prepared, and studied by NMR in DMSO. Protons of the parent peptide had no anomalous chemical shifts, no shallow temperature coefficients for variations of NH chemical shifts with temperature, and no interresidue ROE cross-peaks except for the sequential backbone signals. These results were as expected for a random coil conformation. Conversely, F((2S,3S)-cyclo-M)RF-NH2 gave NMR spectra with indications of a bias toward defined secondary structures in solution. Computer-assisted molecular simulations were carried out to visualize these conformational biases. Thus, parameters for the 2,3-methanoamino acid were developed using literature values for bond vectors from crystallography, and CHARMM defaults. The validity of these parameters was accessed from Ramachandran plots for derivatives of the type Ac-(cyclo-M)-NHMe. These parameters were then used for a comparative quenched molecular dynamics (QMD) study of FMRF-NH2 and F((2S,3S)-cyclo-M)RF-NH2, without invoking constraints from the NMR data. Data (presented as phi, psi dot plots) from the downloaded simulated conformations at 1000 K, and for the energy-minimized forms of these conformations, could be easily rationalized on the basis of reasonable conformational biases about the amino acid residues.