Solution and biologically relevant conformations of enantiomeric 11-cis-locked cyclopropyl retinals.
To gain information on the conformation of the 11-cis-retinylidene chromophore bound to bovine opsin, the enantiomeric pair (2a and 2b) of 11-cis-locked bicyclo[5.1.0]octyl retinal (retCPr) 2 was prepared and its conformation was investigated by NMR, geometry optimization, and CD calculations. This compound is also of interest since it contains a unique moiety in which a chiral cyclopropyl group is flanked by triene and enal chromophores, and hence would clarify the little-known chiroptical contribution of a cyclopropyl ring linked to polyene systems. NMR revealed that the seven-membered ring of retCPr adopts a twist chair conformation. The NMR-derived structure constraints were then used for optimizing the geometry of 2 with molecular mechanics and ab initio methods. This revealed that enantiomer 2a with a 11 beta,12 beta-cyclopropyl group exists as two populations of diastereomers depending on the twist around the 6-s bond; however, the sense of twist around the 12-s is positive in both rotamers. The theoretical Boltzmann-weighted CD obtained with the pi-SCF-CI-DV MO method and experimental spectra were consistent, thus suggesting that the conjugative effect of the cyclopropyl moiety is minimal. It was found that only the beta-cyclopropyl enantiomer 2a, but not the alpha-enantiomer 2b, binds to opsin. This observation, together with earlier retinal analogues incorporation results, led to the conclusion that the chromophore sinks into the N-terminal of the opsin receptor from the side of the 4-methylene and 15-aldehyde, and that the binding cleft accommodates 11-cis-retinal with a slightly positive twist around C12/C13. A reinterpretation of the previously published negative CD couplet of 11,12-dihydrorhodopsin also leads to a chromophoric C12/C13 twist conformation with the 13-Me in front as in 1b. Such a conformation for the chromophore accounts for both the observed biostereoselectivity of retCPr 2a and the observed negative couplet of 11,12-dihydro-Rh7.
Fujimoto
Yukari
Y
Department of Chemistry, Columbia University, New York, New York 10027, USA.
Fishkin
Nathan
N
Pescitelli
Gennaro
G
Decatur
John
J
Berova
Nina
N
Nakanishi
Koji
K
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000737:chemistry; D002417:Cattle; D002942:Circular Dichroism; D003521:Cyclopropanes / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D012172:Retinaldehyde / Q000031:analogs & derivatives* / Q000737:chemistry; D012243:Rhodopsin / Q000737:chemistry; D012996:Solutions; D013237:Stereoisomerism
D001643:Bridged Bicyclo Compounds; D003521:Cyclopropanes; D012996:Solutions; D012243:Rhodopsin; D012172:Retinaldehyde