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Relationships between Th1 or Th2 iNKT cell activity and structures of CD1d-antigen complexes: meta-analysis of CD1d-glycolipids dynamics simulations.

Laurent X, Renault N, Farce A, Chavatte P, Hénon E - PLoS Comput. Biol. (2014)

Bottom Line: A number of potentially bioactive molecules can be found in nature.Associated with the CD1d protein, this α-galactosylceramide 1 (KRN7000) interacts with the T-cell antigen receptor to form a ternary complex that yields T helper (Th) 1 and Th2 responses with opposing effects.One major result is the identification of a specific conformational state of the sugar polar head, which could be correlated, in the present study, to the biological Th2 biased response.

View Article: PubMed Central - PubMed

Affiliation: Intestinal Biotech Development, Faculté de Médecine, Lille, France; Laboratoire de Chimie Thérapeutique EA4481, Université Lille 2, Lille, France.

ABSTRACT
A number of potentially bioactive molecules can be found in nature. In particular, marine organisms are a valuable source of bioactive compounds. The activity of an α-galactosylceramide was first discovered in 1993 via screening of a Japanese marine sponge (Agelas mauritanius). Very rapidly, a synthetic glycololipid analogue of this natural molecule was discovered, called KRN7000. Associated with the CD1d protein, this α-galactosylceramide 1 (KRN7000) interacts with the T-cell antigen receptor to form a ternary complex that yields T helper (Th) 1 and Th2 responses with opposing effects. In our work, we carried out molecular dynamics simulations (11.5 µs in total) involving eight different ligands (conducted in triplicate) in an effort to find out correlation at the molecular level, if any, between chemical modulation of 1 and the orientation of the known biological response, Th1 or Th2. Comparative investigations of human versus mouse and Th1 versus Th2 data have been carried out. A large set of analysis tools was employed including free energy landscapes. One major result is the identification of a specific conformational state of the sugar polar head, which could be correlated, in the present study, to the biological Th2 biased response. These theoretical tools provide a structural basis for predicting the very different dynamical behaviors of α-glycosphingolipids in CD1d and might aid in the future design of new analogues of 1.

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3D-free energy representations of systems Sy1, Sy2, Sy3, Sy12, Sy13 and Sy14.Each isosurface corresponds to points of the 3D-space (φx, φy, φz) with a constant free energy isovalue of 5.4 kcal.mol−1 (9 kBT); replica II (240 ns) at T = 300K.
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pcbi-1003902-g008: 3D-free energy representations of systems Sy1, Sy2, Sy3, Sy12, Sy13 and Sy14.Each isosurface corresponds to points of the 3D-space (φx, φy, φz) with a constant free energy isovalue of 5.4 kcal.mol−1 (9 kBT); replica II (240 ns) at T = 300K.

Mentions: The key results are the following. From a structural point of view, H_OCH and M_AZOL, simulations revealed significant structural changes of the CD1d protein with regard to the other simulations. The replica II (mainly) of the H_OCH simulation shows a modification of the α1 helical structure involving residues 74 to 82 (on the F′ pocket side) as revealed and evidenced by the 1D-FEL analysis (it can be seen on Figure 8, middle panel). Overall, human CD1d in complex with 2 appears to be slightly more fluctuating compared to H_aGAL simulations. More specifically, the residues on the F′ pocket side display a higher mobility in the RMSF analysis of H_OCH. All these changes are very likely due to the truncated sphingosin chain of 2, even though a spacer lipid complements the F′ pocket in this case. The presence of the ligand 8 in the human CD1d protein causes a pronounced enlargement of the 1D-FEL for dihedrals around the residue 153 (residues 151 to 155 of helix α2). This was strongly observed for all three replicas of the M_AZOL system, compared to the M_aGAL one. This clearly shows that the replacement of an amide function with a triazole group significantly increases the flexibility of the α2 helix and consequently disturbs the OTAN hydrogen bond network, which involves the residues Asp151 and Thr154 (helix α2, human numbering). A polar head destabilization is then expected (discussed hereafter). Concerning the ligand 7, no CD1d structural change has been observed here. In spite of the two aforementioned structural changes, absolutely no CD1d difference has been observed concerning the binding footprint and the inter-helix distance between all these systems, which could have explained a Th2 bias.


Relationships between Th1 or Th2 iNKT cell activity and structures of CD1d-antigen complexes: meta-analysis of CD1d-glycolipids dynamics simulations.

Laurent X, Renault N, Farce A, Chavatte P, Hénon E - PLoS Comput. Biol. (2014)

3D-free energy representations of systems Sy1, Sy2, Sy3, Sy12, Sy13 and Sy14.Each isosurface corresponds to points of the 3D-space (φx, φy, φz) with a constant free energy isovalue of 5.4 kcal.mol−1 (9 kBT); replica II (240 ns) at T = 300K.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222593&req=5

pcbi-1003902-g008: 3D-free energy representations of systems Sy1, Sy2, Sy3, Sy12, Sy13 and Sy14.Each isosurface corresponds to points of the 3D-space (φx, φy, φz) with a constant free energy isovalue of 5.4 kcal.mol−1 (9 kBT); replica II (240 ns) at T = 300K.
Mentions: The key results are the following. From a structural point of view, H_OCH and M_AZOL, simulations revealed significant structural changes of the CD1d protein with regard to the other simulations. The replica II (mainly) of the H_OCH simulation shows a modification of the α1 helical structure involving residues 74 to 82 (on the F′ pocket side) as revealed and evidenced by the 1D-FEL analysis (it can be seen on Figure 8, middle panel). Overall, human CD1d in complex with 2 appears to be slightly more fluctuating compared to H_aGAL simulations. More specifically, the residues on the F′ pocket side display a higher mobility in the RMSF analysis of H_OCH. All these changes are very likely due to the truncated sphingosin chain of 2, even though a spacer lipid complements the F′ pocket in this case. The presence of the ligand 8 in the human CD1d protein causes a pronounced enlargement of the 1D-FEL for dihedrals around the residue 153 (residues 151 to 155 of helix α2). This was strongly observed for all three replicas of the M_AZOL system, compared to the M_aGAL one. This clearly shows that the replacement of an amide function with a triazole group significantly increases the flexibility of the α2 helix and consequently disturbs the OTAN hydrogen bond network, which involves the residues Asp151 and Thr154 (helix α2, human numbering). A polar head destabilization is then expected (discussed hereafter). Concerning the ligand 7, no CD1d structural change has been observed here. In spite of the two aforementioned structural changes, absolutely no CD1d difference has been observed concerning the binding footprint and the inter-helix distance between all these systems, which could have explained a Th2 bias.

Bottom Line: A number of potentially bioactive molecules can be found in nature.Associated with the CD1d protein, this α-galactosylceramide 1 (KRN7000) interacts with the T-cell antigen receptor to form a ternary complex that yields T helper (Th) 1 and Th2 responses with opposing effects.One major result is the identification of a specific conformational state of the sugar polar head, which could be correlated, in the present study, to the biological Th2 biased response.

View Article: PubMed Central - PubMed

Affiliation: Intestinal Biotech Development, Faculté de Médecine, Lille, France; Laboratoire de Chimie Thérapeutique EA4481, Université Lille 2, Lille, France.

ABSTRACT
A number of potentially bioactive molecules can be found in nature. In particular, marine organisms are a valuable source of bioactive compounds. The activity of an α-galactosylceramide was first discovered in 1993 via screening of a Japanese marine sponge (Agelas mauritanius). Very rapidly, a synthetic glycololipid analogue of this natural molecule was discovered, called KRN7000. Associated with the CD1d protein, this α-galactosylceramide 1 (KRN7000) interacts with the T-cell antigen receptor to form a ternary complex that yields T helper (Th) 1 and Th2 responses with opposing effects. In our work, we carried out molecular dynamics simulations (11.5 µs in total) involving eight different ligands (conducted in triplicate) in an effort to find out correlation at the molecular level, if any, between chemical modulation of 1 and the orientation of the known biological response, Th1 or Th2. Comparative investigations of human versus mouse and Th1 versus Th2 data have been carried out. A large set of analysis tools was employed including free energy landscapes. One major result is the identification of a specific conformational state of the sugar polar head, which could be correlated, in the present study, to the biological Th2 biased response. These theoretical tools provide a structural basis for predicting the very different dynamical behaviors of α-glycosphingolipids in CD1d and might aid in the future design of new analogues of 1.

Show MeSH