The amide III region of the peptide infrared and Raman spectra has been used to determine the relative populations of the three major backbone conformations (PII, ß, and ?R) in 19 amino acid dipeptides. The results provide a benchmark for force field or other methods of predicting backbone conformations in flexible peptides. There are three resolvable backbone bands in the amide III region. The major population is either PII or ß for all dipeptides except Gly, whereas the ?R population is measurable but always minor (? 10%) for 18 dipeptides. (The Gly ?,? map is complex and so is the interpretation of the amide III bands of Gly.) There are substantial differences in the relative ß and PII populations among the 19 dipeptides. Theband frequencies have been assigned as PII, 1,317-1,306 cm-1; ?R, 1,304-1,294 cm-1; and ß, 1,294-1,270 cm-1. The three bands were measured by both attenuated total reflection spectroscopy and by Raman spectroscopy. Consistent results, both for band frequency and relative population, were obtained by both spectroscopic methods. The ß and PII bands were assigned fromthe dependence of the 3J(HN,H?) coupling constant (known for all 19 dipeptides) on the relative ß population. The PII band assignment agrees with one made earlier from Raman optical activity data. The temperature dependencesof the relative ß and PII populations fit the standard model with Boltzmann-weighted energies for alanine and leucine between 30 and 60?°C.
COBISS.SI-ID: 4611098
Rational design is applied in the discovery of novel lead drugs. Its rapid development is mainly attributed to the tremendous advancements in the computer science, statistics, molecular biology, biophysics, biochemistry, medicinal chemistry, pharmacokinetics and pharmacodynamics experienced in the last few decades. The promising feature that characterizes the application of rational drug design is that it uses for developing potential leads in drug discovery all known theoretical and experimental knowledge of the system understudy. The utilization of the knowledge of the molecular basis of the system ultimately aims to reduce human power cost, time saving and laboratory expenses in the drug discovery. In this review paper various strategies applied for systems which include: (i) absence of knowledge of the receptor active site; (ii) the knowledge of a homology model of a receptor, (iii) the knowledge of the experimentally determined (i.e. X-ray crystallography, NMR spectroscopy) coordinates of the active site of the protein in absence and (iv) the presence of the ligand will be analyzed.
COBISS.SI-ID: 4671770
The two new synthetic analogues of the MBP83-99 epitope substituted at Lys91 (primary TCR contact) with Phe [MBP83-99 (Phe91)] or Tyr [MBP83-99 (Tyr91)], have been structurally elucidated using 1D and 2D high resolution NMR studies. The conformational analysis of the two altered peptide ligands (APLs) has been performed and showed that they adopt a linear and extended conformation which is in agreement with the structural requirements of the peptides that interact with the HLA-DR2 and TCR receptors. In addition, Molecular Dynamics (MD) simulations of the two analogues in complex with HLA-DR2 (DRA, DRB1*1501) and TCR were performed. Similarities and differences of the binding motif of the two analogues were observed which provide a possible explanation of their biological activity. Their differences in the binding mode in comparison with the MBP83-99 epitope may also explain their antagonistic versus agonistic activity. The obtained results clearly indicate that substitutions in crucial amino acids (TCR contacts) in combination with the specific conformational characteristics of the MBP83-99 immunodominant epitope lead to an alteration of their biological activity. These results make the rational drug design intriguing since the biological activity is very sensitive to the substitution and conformation of the mutated MBP epitopes.
COBISS.SI-ID: 4772122