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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.

Show MeSH
HLA-DRβ1* residues involved in Pocket 1, 4, 6, 9 formation and differences with Aona DRβ.Molecular surface of amino acids involved in Pocket 1, 4, 6 and 9 formation (α-chain in pink and β-chain in blue). Differences between HLADRβ1* and Aona DR are shown in red. The amino acids forming the pockets are shown on top of each one. A.B.C.D. Spz 25608.37 mHABP (yellow) fitting into HLADRβ1*0404/0401. The βV86 (red) is the dimorphic variant present in Pocket 1 in some HLA-DRβ1* molecules, showing that there were no differences between HLADRβ1*0422 and Aona DRβ3*0603 in this pocket. E. The same held true for HLADRβ1*0301 and Aona DRβ1*0305 in this pocket. G. Aona DRβ1*0305 Fβ9E (in red) replacement in Pocket 6 was located far away from Pocket 6 side wall; it therefore had no impact on mHABP binding when compared to HLADRβ1*0301. H. The 2 replacements observed between Aona DRβ1*0305, HLADRβ1*0301 (Fβ9E and Yβ37N, both in red) had no impact in Pocket 9 since they were located far away from this pocket’s floor. These mHABPs were thus very similar and could be used for human immunisations without any further modifications.
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pone.0123249.g006: HLA-DRβ1* residues involved in Pocket 1, 4, 6, 9 formation and differences with Aona DRβ.Molecular surface of amino acids involved in Pocket 1, 4, 6 and 9 formation (α-chain in pink and β-chain in blue). Differences between HLADRβ1* and Aona DR are shown in red. The amino acids forming the pockets are shown on top of each one. A.B.C.D. Spz 25608.37 mHABP (yellow) fitting into HLADRβ1*0404/0401. The βV86 (red) is the dimorphic variant present in Pocket 1 in some HLA-DRβ1* molecules, showing that there were no differences between HLADRβ1*0422 and Aona DRβ3*0603 in this pocket. E. The same held true for HLADRβ1*0301 and Aona DRβ1*0305 in this pocket. G. Aona DRβ1*0305 Fβ9E (in red) replacement in Pocket 6 was located far away from Pocket 6 side wall; it therefore had no impact on mHABP binding when compared to HLADRβ1*0301. H. The 2 replacements observed between Aona DRβ1*0305, HLADRβ1*0301 (Fβ9E and Yβ37N, both in red) had no impact in Pocket 9 since they were located far away from this pocket’s floor. These mHABPs were thus very similar and could be used for human immunisations without any further modifications.

Mentions: The highly resonant and hydrophobic structure of aromatic residues (Phe in p1) enabled fitting into highly hydrophobic HLA-DRβ1* Pocket 1 formed by an array of aromatic and apolar residues αF24, αF26, αI31, αF32, αW43 and αF54 in the HLA-DRβ1* α-chain and βY83, βV85, βG86, βF89 in its β-chain [62] (Fig 6A). Phe, Tyr and Trp preference for Pocket 1 could be attributed to the aromatic–aromatic electrostatic interaction [64] with this pocket’s aromatic residues. This was particularly true for side wall, evolutionarily conserved, αW43 [65]; this Pocket 1 space was only limited by the size of the dimorphic Vβ86G variant, rendering this pocket smaller, thereby preferring large apolar residues like Leu, Ile and Val, but tolerating also Phe, but not Tyr, nor Trp (Fig 6A and 6E). This dimorphic variant occurs in all Aotus allelic families [36,66].


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)

HLA-DRβ1* residues involved in Pocket 1, 4, 6, 9 formation and differences with Aona DRβ.Molecular surface of amino acids involved in Pocket 1, 4, 6 and 9 formation (α-chain in pink and β-chain in blue). Differences between HLADRβ1* and Aona DR are shown in red. The amino acids forming the pockets are shown on top of each one. A.B.C.D. Spz 25608.37 mHABP (yellow) fitting into HLADRβ1*0404/0401. The βV86 (red) is the dimorphic variant present in Pocket 1 in some HLA-DRβ1* molecules, showing that there were no differences between HLADRβ1*0422 and Aona DRβ3*0603 in this pocket. E. The same held true for HLADRβ1*0301 and Aona DRβ1*0305 in this pocket. G. Aona DRβ1*0305 Fβ9E (in red) replacement in Pocket 6 was located far away from Pocket 6 side wall; it therefore had no impact on mHABP binding when compared to HLADRβ1*0301. H. The 2 replacements observed between Aona DRβ1*0305, HLADRβ1*0301 (Fβ9E and Yβ37N, both in red) had no impact in Pocket 9 since they were located far away from this pocket’s floor. These mHABPs were thus very similar and could be used for human immunisations without any further modifications.
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Related In: Results  -  Collection

License
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pone.0123249.g006: HLA-DRβ1* residues involved in Pocket 1, 4, 6, 9 formation and differences with Aona DRβ.Molecular surface of amino acids involved in Pocket 1, 4, 6 and 9 formation (α-chain in pink and β-chain in blue). Differences between HLADRβ1* and Aona DR are shown in red. The amino acids forming the pockets are shown on top of each one. A.B.C.D. Spz 25608.37 mHABP (yellow) fitting into HLADRβ1*0404/0401. The βV86 (red) is the dimorphic variant present in Pocket 1 in some HLA-DRβ1* molecules, showing that there were no differences between HLADRβ1*0422 and Aona DRβ3*0603 in this pocket. E. The same held true for HLADRβ1*0301 and Aona DRβ1*0305 in this pocket. G. Aona DRβ1*0305 Fβ9E (in red) replacement in Pocket 6 was located far away from Pocket 6 side wall; it therefore had no impact on mHABP binding when compared to HLADRβ1*0301. H. The 2 replacements observed between Aona DRβ1*0305, HLADRβ1*0301 (Fβ9E and Yβ37N, both in red) had no impact in Pocket 9 since they were located far away from this pocket’s floor. These mHABPs were thus very similar and could be used for human immunisations without any further modifications.
Mentions: The highly resonant and hydrophobic structure of aromatic residues (Phe in p1) enabled fitting into highly hydrophobic HLA-DRβ1* Pocket 1 formed by an array of aromatic and apolar residues αF24, αF26, αI31, αF32, αW43 and αF54 in the HLA-DRβ1* α-chain and βY83, βV85, βG86, βF89 in its β-chain [62] (Fig 6A). Phe, Tyr and Trp preference for Pocket 1 could be attributed to the aromatic–aromatic electrostatic interaction [64] with this pocket’s aromatic residues. This was particularly true for side wall, evolutionarily conserved, αW43 [65]; this Pocket 1 space was only limited by the size of the dimorphic Vβ86G variant, rendering this pocket smaller, thereby preferring large apolar residues like Leu, Ile and Val, but tolerating also Phe, but not Tyr, nor Trp (Fig 6A and 6E). This dimorphic variant occurs in all Aotus allelic families [36,66].

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