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Results and DiscussionThe three-dimensional structures of both analogues studied were determined in AMBER9.0 [2] force field using ensemble-averaged molecular dynamics with the locally enhancedsampling (LES) option. The calculations were performed in an explicit DPC micelle. Theobtained conformational ensembles of both peptides were clustered into families with anrms deviation cut-off of 1.8 Å over the 1-6 C atoms (Table 1 and Figure 1).The common feature of I and II are -turns at positions 2,3; 3,4 and/or 4,5. Theexistence of -turns in cyclic part of molecules is in good agreement with experimentaldata. The C-terminus of II is additionally involved in -turn in Cys 6 -Gly 9 fragment, whichis a consequence of replacement of L-Arg with its enatiomer D. It is worth to highlight, thatthis simple modification changes a very weak oxytocin agonist (analogue I) into moderateantagonists (analogue II). Nevertheless, various pharmacological profile of peptides israther a result of different mutual arrangement of aromatic residues in positions 2 and 3than the changes of Arg 8 configuration from L to D, most of all that the Arg is believed tobe crucial for interactions with vasopressin receptors and not with oxytocin one [3]. In thecase of I, the positively charged guanidine group of Arg 8 displays tendency to be directedto aromatic side chain of Ica 2 , which may result in cation- interactions [4]. This type ofinteractions may have influence on orientation of Ica 2 side chain of I and indirectly may bea reason of different activity.The analysis of interactions of both peptides with DPC micelle shows that I is moredeeply immersed into the micelle core than II. The differences are primarily observed forC-terminal part of molecules.Our results offer new information about structure-activity relationship of AVPanalogues and may be profitably used for the design of new analogues with betterpharmacological profiles.Fig. 1. Stereoviews of the conformational ensembles of [Mpa 1 ,L-Ica 2 ]AVP (I): cluster I (A)and cluster II (B), and [Mpa 1 ,L-Ica 2 ,D-Arg 8 ]VP (II): cluster I (C), cluster II (D), cluster III(E) and cluster IV (F). RMSD 1-6 = 0.272, 0.451, 0.507, 0.658, 0.471 and 0.385 Å for C αatoms, respectively.AcknowledgmentsThis work was supported by the Polish Scientific Research Committee Grant No. N N204 181736grant and the University of Gdańsk, DS. 8453-4-0169-0 and BW. 8372-5-0648-0. The calculationswere carried out in the Academic Computer Centre (TASK) in Gdańsk, Poland.References1. Wymore, T., Gao, X., Wong, T. J. Mol. Struct. 485, 195-206 (1999).2. Case, D., Darden, T., Cheatham, T., Simmerling, C., Wang, J., Duke, R., Luo, R., Merz, K.,Pearlman, D., Crowley, M., Walker, R. AMBER 9, University of California, San Francisco (2006).3. Postina, R., Kojro, E., Fahrenholz, F. J. Biol. Chem. 271, 31593-31601 (1996).4. Shi, Z., Olson, C.A., Kallenbach, N.R. JACS 124, 3284-3291 (2002).429