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  • 1. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Defended by Guillem Revilla López Barcelona, February 17 th MMXI
  • 2. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI Index: 1. Introduction 2. Objectives 3. Thematic subsections 3.1. Characterization of non-coded amino acids 3.2. Engineering of bioinspired systems 3.3. Design of a non-coded amino acid data base 4. Conclusions
  • 3. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI Index: 1. Introduction 2. Objectives 3. Thematic subsections 3.1. Characterization of non-coded amino acids 3.2. Engineering of bioinspired systems 3.3. Design of a non-coded amino acid data base 4. Conclusions
  • 4. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 1. Introduction What is nanotechnology? Nanotechnology is a branch of science that integrates many other disciplines such as chemistry, physics and biology to study matter in the scale of nanometer. Who were the first ones to describe and define the term Nanotechnology ? Prof. Richard P. Feymann “ Plenty of room at the Bottom ” (1958) Prof. Norio Taniguchi “ On the basic concept of nano-technology ” (1974) Study of matter in a scale of work from 1 to 100 nm
  • 5. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 1. Introduction What does it make Nanotechnology important? New material properties: ● Self-aggregation ● Information storage ● Self-replication ● Electrical conduction ● Molecular recognition What did enable the take off of Nanotechnology? Technical advances such as: ● Scanning Tunnelling Microscopy (STM) ● Developments in computational chemistry ● Atomic Force Microscopy (AFM)
  • 6. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 1. Introduction Which are the hotspot fields of nanotechnology? Nanoelectronics Bionanotechnology Protein engineering Nanodiagnostics
  • 7. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 1. Introduction COMPUTATIONAL CHEMISTRY QM MM QM/MM Ab initio DFT Semi-Empirical td- DFT HF Post- HF: MP Classical potential MD SA-MD REMD
  • 8. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 1. Introduction QM ● Electronic structure ● Big systems ● Electron density ● High complexity ● Limited by size and complexity of the system ● No electronic structure MM QM/MM ● Big systems ● High complexity ● Accurate electronic description of a part of the system
  • 9. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 1. Introduction
  • 10. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 1. Introduction
  • 11. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI Index: 1. Introduction 2. Objectives 3. Thematic subsections 3.1. Characterization of non-coded amino acids 3.2. Engineering of bioinspired systems 3.3. Design of a non-coded amino acid data base 4. Conclusions
  • 12. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 2. Objectives
    • To design and characterize the conformational properties of arginine surrogates. Among them, the conformational properties of those derived from proline and from Ac 5 c will be assessed. The role of the solvent polarity and the guanidium group over their structural preferences will be studied.
    • To characterize structurally indoline carboxylic acid (Inc) and α -methyl indoline carboxylic acid ( α MeInc) as proline surrogates and to study the influence of the used theoretical method in the energy assessment of conformational preferences.
    • To elucidate the preferred conformations of phenylazophenylalanine (PAP) and its optical behavior. In order to correlate the optical properties with the conformational preferences, such features for the new amino acid will be compared with those for azobenzene.
    • To improve the homing peptide activity of natural home peptide CREKA by a selective replacement using non-coded engineered amino acid previously studied (C c 5 R EKA). The homing activity of the synthetic peptide will be evaluated by exploring its conformational behavior under different conditions and compared to those of the wild type peptide.
  • 13. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 2. Objectives
    • To simulate the effect of the hypercrowed environment over the conformational landscape of CREKA linked to different kinds of surfaces. The detected structural differences between isolation, crowed environment and surface nature are evaluated in terms of the conformational variability shown by CREKA in every case.
    • To study the conformational dynamics of an engineered peptide. This new molecular hybrid is constituted by an engineered β-amyloid fragment that features thienylalanines instead of phenylalanines. The inner structural properties of the new material will be compared with experimental data in terms of conformational restrictions coming from NMR experiments.
    • To develop a coherent systematic data base that compiles all available structural information of non-coded amino acids, which will be acquired from high level theoretical calculations and, if available, high resolution experimental data. The information will be graphically presented in terms of structural features of each amino acid, easing its use in material science and biomedicine.
  • 14. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI Index: 1. Introduction 2. Objectives 3. Thematic subsections 3.1. Characterization of non-coded amino acids 3.2. Engineering of bioinspired systems 3.3. Design of a non-coded amino acid data base 4. Conclusions
  • 15. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI Arginine features: ● Charged side chain ● High mobility for the side chain A c 5c features: ● Reduced conformational variability ● Bulky side chain Φ Ψ c5Arg + 3.1. Characterization of non-coded amino acids: 3.1.1. Characterization of non-coded amino acids: c5Arg Trans Cis Revilla-lopez G. & co-workers. J. Org. Chem , 74 , 2009
  • 16. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.1. Characterization of non-coded amino acids: 3.1.1. Characterization of non-coded amino acids: c5Arg Conformational exploration of Ac- t -L-c5Arg-NHMe Minima ΔE α L/ γ ’ E/g-t 0 α L/ γ ’ E/g-t 1.6 α L/ γ ’ E/tg+ 2.5 C 7 eq / α E/tg+ 5.2 ΔG gp ΔG wat ΔG chcl3 0 1.6 2.8 6.4 3.2 4.8 0 1.3 2.0 3.1 0 1.5 Revilla-lopez G. & co-workers. J. Org. Chem , 74 , 2009 Calculation level: B3LYP/6-311+G(d,p) . Energies in kcal/mol
  • 17. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.1. Characterization of non-coded amino acids: 3.1.1. Characterization of non-coded amino acids: c5Arg Conformational exploration of Ac- c -L-c5Arg-NHMe Minima ΔE α L/ α E/g+g+ 0 α L/ α E/g+t 0.5 α L/ α E/tg- 1.4 C 7 eq / α E/tg- 2.3 ΔG gp ΔG wat ΔG chcl3 2.0 0 2.1 3.4 4.6 4.9 0 4.1 2.4 3.1 0 3.3 Revilla-lopez ,G. & co-workers. J. Org. Chem , 74 , 2009 Calculation level: B3LYP/6-311+G(d,p). Energies in kcal/mol 1.847 Å 150.1º 1.664 Å 174.8º 1.907 Å 141.1º 2.051 Å 134.6º 1.723 Å 173.9º 1.732 Å 156.5º
  • 18. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.1. Characterization of non-coded amino acids: 3.1.2. Characterization of non-coded amino acids: ( β Pro)Arg Arginine features: ● Charged side chain ● High mobility for the side chain Proline features: ● Main chain low variability ● Bulky side chain + Trans Cis Revilla-lopez ,G. & co-workers. J. Chem. Inf. Model. , 50 , 2010 (βPro) Arg
  • 19. Calculation level: B3LYP/6-31+G(d,p) . Energies in kcal/mol 3.1. Characterization of non-coded amino acids: 3.1.2. Characterization of non-coded amino acids: ( β Pro)Arg A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI Conformational exploration of Ac- t -( β Pro)Arg-NHMe -180 180 -120 120 0 180 120 0 -120 -180 γ D α D ε D ε D δ D δ D β DL β DL β DL β DL δ L δ L γ L α L ε L ε L Minima ΔE Φ Ψ γ L/ [u] /s-g+t 0 γ L/ [u] /g-g-s+ 1.1 γ L/ [u] /g-g-s- α L/ [u] /s-g+t 1.5 2.1 ΔG gp 0.9 2.6 2.0 ΔG ccl4 1.2 0.6 1.5 ΔG chcl3 2.5 0.3 1.9 α L/ [u] /g-tg- 3.5 0 4.1 0 1.2 0.5 0 ΔG wat 6.5 2.6 4.9 2.7 0 α L γ L 1.793 Å 151.3° 1.628 Å 176.2° 1.640 Å 173.7° 1.820 Å 150.0° 1.653 Å 164.3° 1.827 Å 150.6° 1.607 Å 173.0° 1.688 Å 170.2° Revilla-lopez ,G. & co-workers. J. Chem. Inf. Model. , 50 , 2010
  • 20. 3.1. Characterization of non-coded amino acids: 3.1.2. Characterization of non-coded amino acids: ( β Pro)Arg A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI Conformational exploration of Ac- c -( β Pro)Arg-NHMe -180 180 -120 120 0 180 120 0 -120 -180 γ D α D ε D ε D δ D δ D β DL β DL β DL β DL δ L δ L γ L α L ε L ε L Minima ΔE Φ Ψ α L/ [d] /g+g-t 0 α L/ [d] /g+ts+ 1.3 γ L/ [d] /s-g+t 2.0 ΔG gp 0.0 2.2 4.4 ΔG ccl4 0 0.2 4.4 ΔG chcl3 1.1 0 6.5 ΔG wat 2.1 0 9.4 α L γ L 1.595 Å 173.4° 1.570 Å 175.5° 1.869Å 148.5° Revilla-lopez G. & co-workers. J. Chem. Inf. Model. , 50 , 2010 Calculation level: B3LYP/6-31+G(d,p) . Energies in kcal/mol 1.687Å 172.8°
  • 21. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.1. Characterization of non-coded amino acids: 3.1.3. Characterization of non-coded amino acids: Inc Benzene features: ● Delocalized π -electrons ● Rigid planar geometry + Inc Proline features: ● Main chain low variability ● Bulky side chain Cis-Inc Trans-Inc Warrern J.G. & co-workers. J. Phys. Chem. B. , 114 , 2010
  • 22. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.1. Characterization of non-coded amino acids: 3.1.3. Characterization of non-coded amino acids: α MeInc Trans- α MeInc Cis- α MeInc Warrern J.G. & co-workers. J. Phys. Chem. B. , 114 , 2010
  • 23. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.1. Characterization of non-coded amino acids: 3.1.3. Characterization of non-coded amino acids: Inc Gas phase optimized & single point energy calculations t- γ L c- α L c- ε L Δ E 0 3.1 7.3 Δ G gp 0 1.9 5.5 Δ G CCl4 0 1.8 3.2 Δ G CHCl3 0 1.3 0.3 Δ G wat 5.5 5.7 0 A 19.9 P 164.3 A 20.6 P 154.7 A 15.7 P 158.1 Calculation level: B3LYP/6-31+G(d,p). Energies in kcal/mol Warrern J.G. & co-workers. J. Phys. Chem. B. , 114 , 2010
  • 24. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.1. Characterization of non-coded amino acids: 3.1.3. Characterization of non-coded amino acids: α Me Inc Gas phase optimized & single point energy calculations t- γ L c- α L t- α L t- ε L c- ε L Δ E 0 3.5 4.6 4.2 7.0 Δ G gp 0 2.2 3.7 3.8 6.0 Δ G CCl4 0 0.9 2.8 2.9 3.8 Δ G CHCl3 0 0.2 1.5 2.3 1.6 Δ G wat 2.8 0 1.6 3.4 1.2 A 22.6 P 161.2 A 14.0 P -23.5 A 19.3 P -21.2 A 20.0 P -24.1 A 22.3 P -25.6 Calculation level: B3LYP/6-31+G(d,p). Energies in kcal/mol Warrern J.G. & co-workers. J. Phys. Chem. B. , 114 , 2010
  • 25. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.1. Characterization of non-coded amino acids: 3.1.3. Characterization of non-coded amino acids: Inc & α Me Inc ---- 0.0 0.0 5.7 ---- Inc ΔG * SCRF ΔG QM/MM t- ε L t- γ L c- ε L c- α L c- γ L 0.0 1.3 0.0 0.2 2.3 t- α L t- γ L t- ε L c- α L c- ε L α Me Inc ΔG * SCRF 0.0 1.2 1.4 0.0 1.2 ΔG QM/MM 0.0 0.8 ---- 0.0 ---- ΔG SCRF ΔG SCRF 2.7 0.0 0.0 1.6 ---- 0.0 1.8 0.9 0.0 0.5 Warrern J.G. & co-workers. J. Phys. Chem. B. , 114 , 2010 ΔG * SCRF is single point calculation. Energies in kcal/mol
  • 26. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.1. Characterization of non-coded amino acids: 3.1.4. Characterization of non-coded amino acids: PAP Phenylalanine features: ● Bulky aromatic side chain Azobenzene features: ● Photoisomerization between cis and trans isomers + Trans Cis Revilla-López G. & co-workers. J. Phys. Chem. B. , in press , 2011
  • 27. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.1. Characterization of non-coded amino acids: 3.1.4. Characterization of non-coded amino acids: PAP Minima Δ E Δ G gp t- β DL -tg+ 0 0 3.0 Δ G wat t- γ L -g-s+ 0.4 0.6 2.8 t- δ L -g+g+ 1.6 1.1 3.3 t- γ L -g-s+ 2.7 2.0 0 γ D α D ε D ε D δ D δ D β DL β DL β DL β DL δ L δ L γ L α L ε L ε L Calculation level: B3LYP/6-311+G(d,p) . Energies in kcal/mol Δ E ( Φ , Ψ ) Ac-L-(t)PAP-NHMe gas phase Revilla-López G. & co-workers. J. Phys. Chem. B. , in press , 2011 t- γ D -g-s+ 1.8 2.2 3.1
  • 28. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.1. Characterization of non-coded amino acids: 3.1.4. Characterization of non-coded amino acids: PAP Δ E ( Φ , Ψ ) Ac-L-(c)PAP-NHMe gas phase Minima Δ E Δ G gp Δ G wat γ D α D ε D ε D δ D δ D β DL β DL β DL β DL δ L δ L γ L α L ε L ε L Calculation level: B3LYP/6-311+G(d,p) . Energies in kcal/mol Revilla-López G. & co-workers. J. Phys. Chem. B. , in press , 2011 c- β DL -tg+ 0.2 0 3.5 c- γ L -tg+ 0.0 0.5 1.6 c- β DL -g-s+ 1.6 0.5 0 c- γ D -g-s+ 1.7 2.3 2.0 c- α D -g-s+ 4.3 4.3 0.6 c- α L -tg+ 5.6 5.0 1.1 c- δ D -tg+ 6.5 6.2 0.9
  • 29. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.1. Characterization of non-coded amino acids: 3.1.4. Characterization of non-coded amino acids: PAP. Dipolar momentum differences γ D α D ε D ε D δ D δ D β DL β DL β DL β DL δ L δ L γ L α L ε L ε L μ ( Φ , Ψ ) Ac-L-(c)PAP-NHMe - μ ( Φ , Ψ ) Ac-L-(t)PAP-NHMe Calculation level: B3LYP/6-311+G(d,p) . Units are in Debyes Revilla-López G. & co-workers. J. Phys. Chem. B. , in press , 2011
  • 30. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.1. Characterization of non-coded amino acids: 3.1.4. Characterization of non-coded amino acids: PAP  np* =  np* (  ,  ) Ac-L-(c)PAP-NHMe  pp* =  pp* (  ,  ) Ac-L-(c)PAP-NHMe  pp* =  pp* (  ,  ) Ac-L-(t)PAP-NHMe  np* =  np* (  ,  ) Ac-L-(t)PAP-NHMe BOLTZMANN AVERAGE Trans  np* 485 nm BATHOCHROMIC SHIFT  pp* 268 nm HYPSOCHROMIC SHIFT AZOBENZENE Trans Cis  np* 480 nm  np* 484 nm  pp* 269 nm  pp* 266 nm Wavelenghts in nm Calculation level: BMK/6-311+G(d,p) Revilla-López G. & co-workers. J. Phys. Chem. B. , in press , 2011 BOLTZMANN AVERAGE Cis  np* 479 nm HYPSOCHROMIC SHIFT  pp* 270 nm BATHOCHROMIC SHIFT
  • 31. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.1. Characterization of non-coded amino acids: 3.1.5. Characterization of non-coded amino acids: partial conclusions ● c 5 Arg shows a clear tendency towards backbone helical conformations without regard to neither the polarity of the solvent nor the arrangement of the side chain. ● (βPro)Arg has a strong tendency to adopt backbone helical conformations, especially in water. ● Side chain to backbone interactions play a major role in the stabilization of minima in c 5 Arg and (βPro)Arg. ● Trans configuration for the first peptide bond is preferred for Inc and αMeInc in apolar and low polarity environments and cis is the most energetically favored one in aqueous environment. ● An increase in the polarity of the environment tend to stabilize α helical conformations for the cis and trans isomers of α Me Inc. Trans isomer of Inc shows a clear preference for γ L whereas cis isomer shiftes its preferences from α L to ε L as polarity increases. ● Semi-extended conformations are preferred in gas phase for the two isomers of PAP, although in water γ L is preferred for trans isomer and α helical conformations are energetically accessible for the cis isomer. ● Two key optical properties (np* and pp*) show identical behaviour in both azobenzene and PAP.
  • 32. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI Index: 1. Introduction 2. Objectives 3. Thematic subsections 3.1. Characterization of non-coded amino acids 3.2. Engineering of bioinspired systems 3.3. Design of a non-coded amino acid data base 4. Conclusions
  • 33. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI Cysteine - Arginine - Glutamic acid -Lysine- Alanine ( C R E K A ) + + - 3.2. Engineering of bioinspired systems 3.2.1. Engineering of bioinspired systems: C c5R EKA Revilla-López G. & co-workers. ChemPhysChem , in press , 2011
  • 34. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.2. Engineering of bioinspired systems 3.2.1. Engineering of bioinspired systems: C c5R EKA T(K) t(s) Snapshot collection SIMULATED ANNEALING (SA) T(K) t(s) REPLICA EXCHANGE (REMD) Revilla-López G. & co-workers. ChemPhysChem , in press , 2011
  • 35. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.2. Engineering of bioinspired systems 3.2.1. Engineering of bioinspired systems: C c5R EKA REMD SA-MD Revilla-López G. & co-workers. ChemPhysChem , in press , 2011
  • 36. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.2. Engineering of bioinspired systems 3.2.1. Engineering of bioinspired systems: C c5R EKA. Backbone RMSD values <1.30 A 1.30-2.00 A 2.00-3.00 A >3.00 A Revilla-López G. & co-workers. ChemPhysChem , in press , 2011
  • 37. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.2. Engineering of bioinspired systems 3.2.2. Engineering of bioinspired systems: tethered CREKA Curco D. & co-workers. J. Pept. Sci. , 17 , 2011
  • 38. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.2. Engineering of bioinspired systems 3.2.2. Engineering of bioinspired systems: tethered CREKA Energies In kcal/mol Au-S/30 Curco D. & co-workers. J. Pept. Sci. , 17 , 2011
  • 39. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.2. Engineering of bioinspired systems 3.2.2. Engineering of bioinspired systems: tethered CREKA Inert surface Gold surface Single molecule Curco D. & co-workers. J. Pept. Sci. , 17 , 2011
  • 40. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.2. Engineering of bioinspired systems 3.2.2. Engineering of bioinspired systems: tethered CREKA. Backbone RMSD values <1.30 A 1.30-2.00 A 2.00-3.00 A >3.00 A Curco D. & co-workers. J. Pept. Sci. , 17 , 2011
  • 41. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.2. Engineering of bioinspired systems 3.2.3. Engineering of bioinspired systems: ThiThiVLKAA (2)Thi-(2)Thi-Val-Leu-Lys-Ala-Ala ● Engineered fragment of the β -amyloid peptide ● Know aggregation tendency Hamley, I.W. & co-workers. J. Phys. Chem. B , 114 , 2010
  • 42. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.2. Engineering of bioinspired systems 3.2.3. Engineering of bioinspired systems: ThiThiVLKAA NMR restricted Unrestricted Hamley, I.W. & co-workers. J. Phys. Chem. B , 114 , 2010
  • 43. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.2. Engineering of bioinspired systems 3.2.3. Engineering of bioinspired systems: ThiThiVLKAA Unrestricted NMR restricted Hamley, I.W. & co-workers. J. Phys. Chem. B , 114 , 2010
  • 44. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.2. Engineering of bioinspired systems: 3.2.4. Engineering of bioinspired systems: partial conclusions ● C c5R EKA show a restricted conformational profile if compared to that of the wild type peptide. The lowest energy conformations visited by C c5R EKA remain similar to wild type peptide. ● High density of CREKA peptide linked to a surface restricts the conformational variation of the peptide while maintaining lowest energy conformations similar to those found for single peptide. The chemical activity of a surface simulating gold causes a similar effect to that of high density. ● ThiThiVLKAA shows a marked conformational dependance on the concentration .
  • 45. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI Index: 1. Introduction 2. Objectives 3. Thematic subsections 3.1. Characterization of non-coded amino acids 3.2. Engineering of bioinspired systems 3.3. Design of a non-coded amino acid data base 4. Conclusions
  • 46. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.3. Design of a non-coded amino acid data base 3.3.1. Design of a non-coded amino acid data base Revilla-Lopez, G. & co-workers. J. Phys. Chem. B , 114 , 2010 Revilla-Lopez, G. & co-workers. Proteins , in press , 2011
  • 47. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.3. Design of a non-coded amino acid data base 3.3.1. Design of a non-coded amino acid data base CHEMTYPE Non-cyclic quaternary tetrasubstituted amino acid Cyclic quaternary tetrasubstituted amino acid Proline-derived amino acid N-substituted amino acid Diacid retro-amino acid Diamine retro-amino acid Thioamino acid Revilla-Lopez, G. & co-workers. J. Phys. Chem. B , 114 , 2010 Revilla-Lopez, G. & co-workers. Proteins , in press , 2011
  • 48. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.3. Design of a non-coded amino acid data base 3.3.1. Design of a non-coded amino acid data base NCAD is freely available at http :// recerca.upc.edu/imem/index.htm Revilla-Lopez, G. & co-workers. J. Phys. Chem. B , 114 , 2010 Revilla-Lopez, G. & co-workers. Proteins , in press , 2011
  • 49. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.3. Design of a non-coded amino acid data base 3.3.1. Design of a non-coded amino acid data base Wild-type Metionine-Enkephallin Met- Phe - Gly-Gly -Tyr
    • Similar conformational behavior
    • Similar side chain chemical nature
    Revilla-Lopez, G. & co-workers. J. Phys. Chem. B , 114 , 2010 Revilla-Lopez, G. & co-workers. Proteins , in press , 2011
  • 50. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.3. Design of a non-coded amino acid data base 3.3.1. Design of a non-coded amino acid data base Revilla-Lopez, G. & co-workers. J. Phys. Chem. B , 114 , 2010 Revilla-Lopez, G. & co-workers. Proteins , in press , 2011
  • 51. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 3.3. Design of a non-coded amino acid data base 3.3.1. Design of a non-coded amino acid data base: Partial conclusions ● A new data base (NCAD) has been developed to systematic and comprehensively store available information about non-coded amino acids ● NCAD enables multi-factor searches in order to offer an user friendly interface ● NCAD can successfully suggest surrogates for natural occurring amino acids in engineered peptides
  • 52. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Defended by Guillem Revilla López Barcelona, February 17 th MMXI
  • 53. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI Index: 1. Introduction 2. Objectives 3. Thematic subsections 3.1. Characterization of non-coded amino acids 3.2. Engineering of bioinspired systems 3.3. Design of a non-coded amino acid data base 4. Conclusions
  • 54. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 4. Conclusions
    • The conformationally restricted arginine surrogate c 5 Arg shows a clear preference for α-helical backbone conformations due to side chain-main chain interactions involving the guanidium group. The helical conformation is the most energetically accessible, independently of the polarity of the solvent. This conformational trend is featured without regard of the chosen isomer for the side chain arrangement and suggests a strong tendency to be found at i +1 position in β-turns in proteins.
    • The proline-derived arginine analogue ( β Pro)Arg adopts an α-helical conformation for its two side chain isomers in polar and apolar solvents, this preference is maintained in spite of considering thermal agitation. These facts suggest that ( β Pro)Arg has new conformational properties not exactly matching those of proline that allow it to replace arginine in proteins when present at i +1 position in β-turns.
  • 55. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 4. Conclusions
    • Proline derived Inc and αMeInc show a significantly reduced conformational profile in comparison to proline due to the benzene moiety fused to the pyrrol ring. The α-helical conformation is preferred in water for the two compounds whereas γ-turn is adopted in gas phase and chlorinated solvents for both of them, although α-helical is also accessible for αMeInc in the latter solvents as a product of the steric stress induced by the methyl group. A dramatic restriction of the flexibility of the pyrrol ring is also found: no clear envelope forms are indentified, just the α carbon shows a little deviation from the pyrrol plane.
    • The energetics of cis/trans isomerism of the peptidic bond involving pyrrol nitrogen shows a significant variability depending of the chosen solvation model. Single point calculations and optimizations with a continuum model of solvent point to cis isomer as the preferred arrangement whereas trans configuration is the most energetically favored in the QM/MM. Inner structural tension, water entropic contribution and hydrogen bonding ability must be taken into account to explain these divergences.
  • 56. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 4. Conclusions
    • The full conformational landscape of PAP has been investigated for the two isomers of the azobenzenic side chain: both cis and trans tend to adopt semi-extended backbone conformation as the lowest energy one in gas phase. Differences arise as α-helical arrangements become unreachable for trans but not for cis in gas phase, though they are energetically less favored. The solvation with a continuum model of water modifies energetic order for trans that shifts its most favored conformation to γ L , while for cis the global minimum remains a semi-extended conformation and helical conformations increase their stability. The energy difference between cis and trans isomers remains favorable to the latter throughout the energy landscape ranging from 7 to 17 kcal·mol -1 .
    • Two optical properties of PAP have been studied and compared to those for azobenzene: n  * (np) and  * (pp) wavelength transitions are almost identical for azobenzene and PAP. Moreover, variations for those values upon trans to cis isomerization are in clear agreement with data from azobenzene, a bathochromic shift (4 nm) for np and hypsochromic shift (-3 nm) for pp. The variation of  pp =  pp (  ,  ) and  np =  np (  ,  ) is never above 10 nm. All these facts suggest that the incorporation of azobenzene to a peptide scaffold does not alter significantly its optical properties, even if the peptide backbone changes its conformation.
  • 57. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 4. Conclusions
    • Non-coded amino acid c 5 Arg is an optimal replacement for arginine in the homing peptide CREKA to become the engineered peptide C c 5 R EKA. The conformational landscape of C c 5 R EKA shows that the minimal energy conformations are biased towards those reported as bioactive for CREKA. The β-turn centered in second and third residues that is usually depicted by CREKA is stabilized by the conformational preferences of c 5 Arg . This non-coded amino acid also allows the saline bridge interaction between the charged side chains of the central fragments amino acids and should introduce resistance to proteolysis.
    • High density of CREKA peptide linked to a surface restricts conformational variability of the peptide in comparison to infinite dilution. This trend is featured without regard of the chemical activity of the surface. Despite these restraints, the lowest energy conformations found in each case are similar among them, especially for the three amino acids of the central fragment. Intra-molecular interactions of CREKA might play a more significant role than the inter-molecular in the structural preferences of the peptide.
  • 58. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Guillem Revilla López MMXI 4. Conclusions
    • The dynamic conformational behavior of (2-Thi)(2-Thi)VLKAA has been evaluated to ascertain the effect of concentration (i.e. inter-molecular interactions) on the conformational behaviour of the peptide. The results of MD simulations show significant differences in the backbone conformations adopted by the five central amino acids of the peptide depending on the fulfilment of NMR-derived restraints. Those alterations are not translated into major changes in the radius of gyration of the peptide but they cause peptide end-to-end distance to be far less changing in comparison to the unrestrained MD simulation. NMR-derived restraints favours major proximity between the side chains of the two β2-thienylalanine units.
    • In order to rationally gather key information for potential uses of non-coded amino acid in biomedical and material science, a data base (NCAD) has been designed including conformational information obtained at high theoretical level for non-coded amino acid. The data base displays a user-friendly interface that enables searches by conformation, side chain chemical nature, amino acid biological type, publications author, experimental characterization and applied available knowledge. NCAD includes non-coded amino acids form different types: alpha-tetrasubstituted alpha amino acids, diamines and diacids for retropeptides, N-subtituted amino acids and thio-amino acids. The usefulness of the NCAD has been demonstrated through two examples of molecular engineered molecules.
  • 59. A theoretical approach to the engineering of bioinspired systems: design, applications and information management Defended by Guillem Revilla López Barcelona, February 17 th MMXI