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N1 Position (n1 + position)
Selected AbstractsEffect of the N1 residue on the stability of the ,-helix for all 20 amino acidsPROTEIN SCIENCE, Issue 3 2001Duncan A.E. Cochran Abstract N1 is the first residue in an ,-helix. We have measured the contribution of all 20 amino acids to the stability of a small helical peptide CH3CO-XAAAAQAAAAQAAGY-NH2 at the N1 position. By substituting every residue into the N1 position, we were able to investigate the stabilizing role of each amino acid in an isolated context. The helix content of each of the 20 peptides was measured by circular dichroism (CD) spectroscopy. The data were analyzed by our modified Lifson-Roig helix-coil theory, which includes the n1 parameter, to find free energies for placing a residue into the N1 position. The rank order for free energies is Asp,, Ala > Glu, > Glu0 > Trp, Leu, Ser > Asp0, Thr, Gln, Met, Ile > Val, Pro > Lys+, Arg, His0 > Cys, Gly > Phe > Asn, Tyr, His+. N1 preferences are clearly distinct from preferences for the preceding N-cap and ,-helix interior. pKa values were measured for Asp, Glu, and His, and protonation-free energies were calculated for Asp and Glu. The dissociation of the Asp proton is less favorable than that of Glu, and this reflects its involvement in a stronger stabilizing interaction at the N terminus. Proline is not energetically favored at the ,-helix N terminus despite having a high propensity for this position in crystal structures. The data presented are of value both in rationalizing mutations at N1 ,-helix sites in proteins and in predicting the helix contents of peptides. [source] Determination of ,-helix N1 energies after addition of N1, N2, and N3 preferences to helix/coil theoryPROTEIN SCIENCE, Issue 4 2000Jia Ke Sun Abstract Surveys of protein crystal structures have revealed that amino acids show unique structural preferences for the N1, N2, and N3 positions in the first turn of the ,-helix. We have therefore extended helix-coil theory to include statistical weights for these locations. The helix content of a peptide in this model is a function of N-cap, C-cap, N1, N2, N3, C1, and helix interior (N4 to C2) preferences. The partition function for the system is calculated using a matrix incorporating the weights of the fourth residue in a hexamer of amino acids and is implemented using a FORTRAN program. We have applied the model to calculate the N1 preferences of Gln, Val, Ile, Ala, Met, Pro, Leu, Thr, Gly, Ser, and Asn, using our previous data on helix contents of peptides Ac-XAKAAAAKAAGY-CONH2. We find that Ala has the highest preference for the N1 position. Asn is the most unfavorable, destabilizing a helix at N1 by at least 1.4 kcal mol,1 compared to Ala. The remaining amino acids all have similar preferences, 0.5 kcal mol,1 less than Ala. Gln, Asn, and Ser, therefore, do not stabilize the helix when at N1. [source] Synthesis and Biological Testing of N -Aminoimidazole-Based p38, MAP Kinase InhibitorsCHEMMEDCHEM, Issue 7 2010Claudia Bracht Abstract The p38 mitogen-activated protein (MAP) kinase,, plays a central role in the regulation of cellular responses such as differentiation, proliferation, apoptosis, and inflammation. Inhibition of p38 results in decreased synthesis of pro-inflammatory cytokines. To date, diverse p38, inhibitors are in phase,II clinical trials for numerous cytokine-dependent diseases. 2-Sulfanylimidazole derivatives offer advantages over the prototype inhibitor SB,203580, including fewer cytochrome P450 interactions and better kinetic properties. The aim of this study was to develop novel 1,2,4,5-tetrasubstituted pyridinylimidazoles with acyl residues at the imidazole N1 position that can interact with the kinase's hydrophobic region,II (HR,II) or sugar pocket (SP) to improve both selectivity and activity. The substitution pattern was optimized by variation of the acyl moiety at the N1 position of the N -aminoimidazole core. Acylation of the amino function was used for optimization and led to potent p38, MAPK inhibitors. [source] |