Limits...
IMPIPS: the immune protection-inducing protein structure concept in the search for steric-electron and topochemical principles for complete fully-protective chemically synthesised vaccine development.

Patarroyo ME, Bermúdez A, Alba MP, Vanegas M, Moreno-Vranich A, Poloche LA, Patarroyo MA - PLoS ONE (2015)

Bottom Line: Modified high activity binding peptides (mHABP) were thus synthesised to produce a large panel of IMPIPS measuring 26.5 ±3.5Å between the farthest atoms fitting into Pockets 1 to 9 of HLA-DRβ1* structures.They displayed a polyproline II-like (PPIIL) structure with their backbone O and N atoms orientated to establish H-bonds with specific residues from HLA-DRβ1*-peptide binding regions (PBR).Residues having specific charge and gauche+ orientation regarding p3χ1, p5χ2, and p7χ1 angles determined appropriate rotamer orientation for perfectly fitting into the TCR to induce an appropriate immune response.

View Article: PubMed Central - PubMed

Affiliation: Fundación Instituto de Inmunología de Colombia (FIDIC), Bogotá, Colombia; Universidad Nacional de Colombia, Bogotá, Colombia.

ABSTRACT
Determining immune protection-inducing protein structures (IMPIPS) involves defining the stereo-electron and topochemical characteristics which are essential in MHC-p-TCR complex formation. Modified high activity binding peptides (mHABP) were thus synthesised to produce a large panel of IMPIPS measuring 26.5 ±3.5Å between the farthest atoms fitting into Pockets 1 to 9 of HLA-DRβ1* structures. They displayed a polyproline II-like (PPIIL) structure with their backbone O and N atoms orientated to establish H-bonds with specific residues from HLA-DRβ1*-peptide binding regions (PBR). Residues having specific charge and gauche+ orientation regarding p3χ1, p5χ2, and p7χ1 angles determined appropriate rotamer orientation for perfectly fitting into the TCR to induce an appropriate immune response. Immunological assays in Aotus monkeys involving IMPIPS mixtures led to promising results; taken together with the aforementioned physicochemical principles, non-interfering, long-lasting, protection-inducing, multi-epitope, multistage, minimal subunit-based chemically-synthesised peptides can be designed against diseases scourging humankind.

Show MeSH
Comparison of initial and final peptide-bond planes for 25608.37. A, C, E, G, I, K and M.Green cubes indicate initial theoretical positions for 25068.37 regarding PBR residues forming Φ and ψ angles on planes 1 to 9. B., D., F., H., J., L. and N. Final position of these angles reaching the lowest energy to avoid topochemical steric clashes, as measured for the lowest energy conformer, based on 3D structure obtained by 1H-NMR. Most angles were close to -93° ± 25° (Φ) and 134° ± 15° (Ψ), similar to PPIIL. Minimisation values for atom clashes as determined by Ramachandran plot. HLA-DRβ1* classification according to experimental binding to purified molecules, binding motifs and binding registers is shown at the top on the right-hand side.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4400017&req=5

pone.0123249.g004: Comparison of initial and final peptide-bond planes for 25608.37. A, C, E, G, I, K and M.Green cubes indicate initial theoretical positions for 25068.37 regarding PBR residues forming Φ and ψ angles on planes 1 to 9. B., D., F., H., J., L. and N. Final position of these angles reaching the lowest energy to avoid topochemical steric clashes, as measured for the lowest energy conformer, based on 3D structure obtained by 1H-NMR. Most angles were close to -93° ± 25° (Φ) and 134° ± 15° (Ψ), similar to PPIIL. Minimisation values for atom clashes as determined by Ramachandran plot. HLA-DRβ1* classification according to experimental binding to purified molecules, binding motifs and binding registers is shown at the top on the right-hand side.

Mentions: Analysing PPIIL conformation in IMPIPS for a better understanding of its fundamental role led to generalising that there would be a steric clash between H1 and O2 (Fig 4A, green cubes) if initial theoretical atom localisation and Ψ and Φ angle rotation in 25608.37 (Fig 4A) were compared in the lowest energy conformer measurement initial plane 1 and 2 position, taking Phe1 torsion angle Ψ = 0 and Leu3 Φ = 0 (as an example for all Ramachandran plot-based IMPIPS and Φ, Ψ, χ1, χ2 angles and 1H-NMR-determined distances); final 129° Ψ and -80.6° Φ rotation (Fig 4B) would thus have had to be induced to avoid such clash.


IMPIPS: the immune protection-inducing protein structure concept in the search for steric-electron and topochemical principles for complete fully-protective chemically synthesised vaccine development.

Patarroyo ME, Bermúdez A, Alba MP, Vanegas M, Moreno-Vranich A, Poloche LA, Patarroyo MA - PLoS ONE (2015)

Comparison of initial and final peptide-bond planes for 25608.37. A, C, E, G, I, K and M.Green cubes indicate initial theoretical positions for 25068.37 regarding PBR residues forming Φ and ψ angles on planes 1 to 9. B., D., F., H., J., L. and N. Final position of these angles reaching the lowest energy to avoid topochemical steric clashes, as measured for the lowest energy conformer, based on 3D structure obtained by 1H-NMR. Most angles were close to -93° ± 25° (Φ) and 134° ± 15° (Ψ), similar to PPIIL. Minimisation values for atom clashes as determined by Ramachandran plot. HLA-DRβ1* classification according to experimental binding to purified molecules, binding motifs and binding registers is shown at the top on the right-hand side.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4400017&req=5

pone.0123249.g004: Comparison of initial and final peptide-bond planes for 25608.37. A, C, E, G, I, K and M.Green cubes indicate initial theoretical positions for 25068.37 regarding PBR residues forming Φ and ψ angles on planes 1 to 9. B., D., F., H., J., L. and N. Final position of these angles reaching the lowest energy to avoid topochemical steric clashes, as measured for the lowest energy conformer, based on 3D structure obtained by 1H-NMR. Most angles were close to -93° ± 25° (Φ) and 134° ± 15° (Ψ), similar to PPIIL. Minimisation values for atom clashes as determined by Ramachandran plot. HLA-DRβ1* classification according to experimental binding to purified molecules, binding motifs and binding registers is shown at the top on the right-hand side.
Mentions: Analysing PPIIL conformation in IMPIPS for a better understanding of its fundamental role led to generalising that there would be a steric clash between H1 and O2 (Fig 4A, green cubes) if initial theoretical atom localisation and Ψ and Φ angle rotation in 25608.37 (Fig 4A) were compared in the lowest energy conformer measurement initial plane 1 and 2 position, taking Phe1 torsion angle Ψ = 0 and Leu3 Φ = 0 (as an example for all Ramachandran plot-based IMPIPS and Φ, Ψ, χ1, χ2 angles and 1H-NMR-determined distances); final 129° Ψ and -80.6° Φ rotation (Fig 4B) would thus have had to be induced to avoid such clash.

Bottom Line: Modified high activity binding peptides (mHABP) were thus synthesised to produce a large panel of IMPIPS measuring 26.5 ±3.5Å between the farthest atoms fitting into Pockets 1 to 9 of HLA-DRβ1* structures.They displayed a polyproline II-like (PPIIL) structure with their backbone O and N atoms orientated to establish H-bonds with specific residues from HLA-DRβ1*-peptide binding regions (PBR).Residues having specific charge and gauche+ orientation regarding p3χ1, p5χ2, and p7χ1 angles determined appropriate rotamer orientation for perfectly fitting into the TCR to induce an appropriate immune response.

View Article: PubMed Central - PubMed

Affiliation: Fundación Instituto de Inmunología de Colombia (FIDIC), Bogotá, Colombia; Universidad Nacional de Colombia, Bogotá, Colombia.

ABSTRACT
Determining immune protection-inducing protein structures (IMPIPS) involves defining the stereo-electron and topochemical characteristics which are essential in MHC-p-TCR complex formation. Modified high activity binding peptides (mHABP) were thus synthesised to produce a large panel of IMPIPS measuring 26.5 ±3.5Å between the farthest atoms fitting into Pockets 1 to 9 of HLA-DRβ1* structures. They displayed a polyproline II-like (PPIIL) structure with their backbone O and N atoms orientated to establish H-bonds with specific residues from HLA-DRβ1*-peptide binding regions (PBR). Residues having specific charge and gauche+ orientation regarding p3χ1, p5χ2, and p7χ1 angles determined appropriate rotamer orientation for perfectly fitting into the TCR to induce an appropriate immune response. Immunological assays in Aotus monkeys involving IMPIPS mixtures led to promising results; taken together with the aforementioned physicochemical principles, non-interfering, long-lasting, protection-inducing, multi-epitope, multistage, minimal subunit-based chemically-synthesised peptides can be designed against diseases scourging humankind.

Show MeSH