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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.

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Steric-electron effects. 25608.37 (left panel) and 10022.43 (right panel) mHABP residues, displaying hybrid sigma (σ) orbitals (yellow), π and p orbitals perpendicular to them (red, blurred balloons).For 25608.37: A and B. Phe1 displaying π resonance (red—bonds between p orbitals); Ser2 tetrahedron with the two free electron pairs (indicated) showing only the σ orbitals. C. Leu3 (green), showing the tetrahedron framing Cδ1 side-chain and orientation (pointing upwards), only Gly4 plane is shown. D. Glu5 (green), showing the tetrahedron framing Cɣ and trigon with Cδ and resonance between the two O and their corresponding Cδ from the side-chain (blurred red balloons); the electron charge is shown in blurred red orbitals. E. Asn 6 directed to Pocket 6, showing the tetrahedron, a trigon and the electron charge in blurred red. F. Pro 7 in grey and two trigons in green. G. Asn 8 directed toward the TCR with its corresponding p orbitals and its non-bonding free electron pair; Ala9 is also shown in green with a tetrahedron in the same colour. For 10022.43: H. Phe 1 orientation, π resonance and its planes corresponding to peptide bonds. I. His2 showing the π resonance tiara. J. Pro3 cyclic structure with σ orbitals pointing upwards to contact the TCR, and also displaying the tetrahedron formed by the Ser4 side-chain pointing downwards. K. showing the tetrahedrons formed for Gly5 and Ser7 with its two free electron pairs. L. Pro 8 σ electrons pointing upwards and Val9, showing the two tetrahedrons framing Cδ1 and Cδ2 and their apolarity represented in σ-bonds.
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pone.0123249.g005: Steric-electron effects. 25608.37 (left panel) and 10022.43 (right panel) mHABP residues, displaying hybrid sigma (σ) orbitals (yellow), π and p orbitals perpendicular to them (red, blurred balloons).For 25608.37: A and B. Phe1 displaying π resonance (red—bonds between p orbitals); Ser2 tetrahedron with the two free electron pairs (indicated) showing only the σ orbitals. C. Leu3 (green), showing the tetrahedron framing Cδ1 side-chain and orientation (pointing upwards), only Gly4 plane is shown. D. Glu5 (green), showing the tetrahedron framing Cɣ and trigon with Cδ and resonance between the two O and their corresponding Cδ from the side-chain (blurred red balloons); the electron charge is shown in blurred red orbitals. E. Asn 6 directed to Pocket 6, showing the tetrahedron, a trigon and the electron charge in blurred red. F. Pro 7 in grey and two trigons in green. G. Asn 8 directed toward the TCR with its corresponding p orbitals and its non-bonding free electron pair; Ala9 is also shown in green with a tetrahedron in the same colour. For 10022.43: H. Phe 1 orientation, π resonance and its planes corresponding to peptide bonds. I. His2 showing the π resonance tiara. J. Pro3 cyclic structure with σ orbitals pointing upwards to contact the TCR, and also displaying the tetrahedron formed by the Ser4 side-chain pointing downwards. K. showing the tetrahedrons formed for Gly5 and Ser7 with its two free electron pairs. L. Pro 8 σ electrons pointing upwards and Val9, showing the two tetrahedrons framing Cδ1 and Cδ2 and their apolarity represented in σ-bonds.

Mentions: Since molecules’ subatomic electron interactions and their implicit molecular geometry play a fundamental role in their fitting into the HLA-DRβ1 PBR, and therefore in their immunological performance, such characteristics were analysed regarding the best fitting Spz-derived CSP mHABP. This was 25608.37 (4383) (Phe1Ser2Leu3Gly4Glu5Asn6Pro7Asn8Ala9) (Fig 5A) which had high binding capacity (58%) to purified HLA-DRβ1*0401 molecules and had the characteristic binding motifs and binding registers for this allele family [45].


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)

Steric-electron effects. 25608.37 (left panel) and 10022.43 (right panel) mHABP residues, displaying hybrid sigma (σ) orbitals (yellow), π and p orbitals perpendicular to them (red, blurred balloons).For 25608.37: A and B. Phe1 displaying π resonance (red—bonds between p orbitals); Ser2 tetrahedron with the two free electron pairs (indicated) showing only the σ orbitals. C. Leu3 (green), showing the tetrahedron framing Cδ1 side-chain and orientation (pointing upwards), only Gly4 plane is shown. D. Glu5 (green), showing the tetrahedron framing Cɣ and trigon with Cδ and resonance between the two O and their corresponding Cδ from the side-chain (blurred red balloons); the electron charge is shown in blurred red orbitals. E. Asn 6 directed to Pocket 6, showing the tetrahedron, a trigon and the electron charge in blurred red. F. Pro 7 in grey and two trigons in green. G. Asn 8 directed toward the TCR with its corresponding p orbitals and its non-bonding free electron pair; Ala9 is also shown in green with a tetrahedron in the same colour. For 10022.43: H. Phe 1 orientation, π resonance and its planes corresponding to peptide bonds. I. His2 showing the π resonance tiara. J. Pro3 cyclic structure with σ orbitals pointing upwards to contact the TCR, and also displaying the tetrahedron formed by the Ser4 side-chain pointing downwards. K. showing the tetrahedrons formed for Gly5 and Ser7 with its two free electron pairs. L. Pro 8 σ electrons pointing upwards and Val9, showing the two tetrahedrons framing Cδ1 and Cδ2 and their apolarity represented in σ-bonds.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0123249.g005: Steric-electron effects. 25608.37 (left panel) and 10022.43 (right panel) mHABP residues, displaying hybrid sigma (σ) orbitals (yellow), π and p orbitals perpendicular to them (red, blurred balloons).For 25608.37: A and B. Phe1 displaying π resonance (red—bonds between p orbitals); Ser2 tetrahedron with the two free electron pairs (indicated) showing only the σ orbitals. C. Leu3 (green), showing the tetrahedron framing Cδ1 side-chain and orientation (pointing upwards), only Gly4 plane is shown. D. Glu5 (green), showing the tetrahedron framing Cɣ and trigon with Cδ and resonance between the two O and their corresponding Cδ from the side-chain (blurred red balloons); the electron charge is shown in blurred red orbitals. E. Asn 6 directed to Pocket 6, showing the tetrahedron, a trigon and the electron charge in blurred red. F. Pro 7 in grey and two trigons in green. G. Asn 8 directed toward the TCR with its corresponding p orbitals and its non-bonding free electron pair; Ala9 is also shown in green with a tetrahedron in the same colour. For 10022.43: H. Phe 1 orientation, π resonance and its planes corresponding to peptide bonds. I. His2 showing the π resonance tiara. J. Pro3 cyclic structure with σ orbitals pointing upwards to contact the TCR, and also displaying the tetrahedron formed by the Ser4 side-chain pointing downwards. K. showing the tetrahedrons formed for Gly5 and Ser7 with its two free electron pairs. L. Pro 8 σ electrons pointing upwards and Val9, showing the two tetrahedrons framing Cδ1 and Cδ2 and their apolarity represented in σ-bonds.
Mentions: Since molecules’ subatomic electron interactions and their implicit molecular geometry play a fundamental role in their fitting into the HLA-DRβ1 PBR, and therefore in their immunological performance, such characteristics were analysed regarding the best fitting Spz-derived CSP mHABP. This was 25608.37 (4383) (Phe1Ser2Leu3Gly4Glu5Asn6Pro7Asn8Ala9) (Fig 5A) which had high binding capacity (58%) to purified HLA-DRβ1*0401 molecules and had the characteristic binding motifs and binding registers for this allele family [45].

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