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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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Root mean square deviation matrix of H_aGAL (top) and H_CD1d (bottom) simulations.Root mean square deviation (alpha carbons of CD1d α1/α2 helices) of every conformation to all other as a function of time during a 240 ns simulation; replica I, II, III.
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pcbi-1003902-g003: Root mean square deviation matrix of H_aGAL (top) and H_CD1d (bottom) simulations.Root mean square deviation (alpha carbons of CD1d α1/α2 helices) of every conformation to all other as a function of time during a 240 ns simulation; replica I, II, III.

Mentions: First, 2D-RMSD (α1/α2 interface) can be helpful to detect different conformational “substates”. While replicas I and II of H_aGAL show a relative homogenous 2D-RMSD plot (Figure 3), replica III appears to move into two “wide” different conformations. Trajectories of H_CD1d give more contrasted patterns, with replica III showing three dissimilar clusters. The matrix average of RMSD values accurately reflects the level of granularity observed by visual inspection (numbers reported in Figure S2). These plots clearly show that the two CD1d helices can be very stable during 240 ns or in contrast go through several distinct conformational states with a life of a few tens of nanoseconds. Therefore, it seems that one cannot just perform a single 240 ns MD simulation but rather running multiple MD with different starting initial conditions is better to study the interface of the binary complex. Surprisingly, at this stage, though H_CD1d displays slightly more contrasted 2D-RMSD figures, the α1/α2 interface of H_aGAL and H_CD1d does not appear to have greatly differing dynamical behavior.


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)

Root mean square deviation matrix of H_aGAL (top) and H_CD1d (bottom) simulations.Root mean square deviation (alpha carbons of CD1d α1/α2 helices) of every conformation to all other as a function of time during a 240 ns simulation; replica I, II, III.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003902-g003: Root mean square deviation matrix of H_aGAL (top) and H_CD1d (bottom) simulations.Root mean square deviation (alpha carbons of CD1d α1/α2 helices) of every conformation to all other as a function of time during a 240 ns simulation; replica I, II, III.
Mentions: First, 2D-RMSD (α1/α2 interface) can be helpful to detect different conformational “substates”. While replicas I and II of H_aGAL show a relative homogenous 2D-RMSD plot (Figure 3), replica III appears to move into two “wide” different conformations. Trajectories of H_CD1d give more contrasted patterns, with replica III showing three dissimilar clusters. The matrix average of RMSD values accurately reflects the level of granularity observed by visual inspection (numbers reported in Figure S2). These plots clearly show that the two CD1d helices can be very stable during 240 ns or in contrast go through several distinct conformational states with a life of a few tens of nanoseconds. Therefore, it seems that one cannot just perform a single 240 ns MD simulation but rather running multiple MD with different starting initial conditions is better to study the interface of the binary complex. Surprisingly, at this stage, though H_CD1d displays slightly more contrasted 2D-RMSD figures, the α1/α2 interface of H_aGAL and H_CD1d does not appear to have greatly differing dynamical behavior.

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