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Conformational dynamics and ligand binding in the multi-domain protein PDC109.

Kim HJ, Choi MY, Kim HJ, Llinás M - PLoS ONE (2010)

Bottom Line: The effective PDC109-PhC association constant of 28 M(-1), estimated from their potential of mean force is consistent with the experimental result.Principal component analysis of the long timescale MD simulations was compared to the significantly less expensive normal mode analysis of minimized structures.The present study illustrates the use of detailed MD simulations to clarify the energetics of specific ligand-domain interactions revealed by a static crystallographic model, as well as their influence on relative domain motions in a multi-domain protein.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT
PDC109 is a modular multi-domain protein with two fibronectin type II (Fn2) repeats joined by a linker. It plays a major role in bull sperm binding to the oviductal epithelium through its interactions with phosphorylcholines (PhCs), a head group of sperm cell membrane lipids. The crystal structure of the PDC109-PhC complex shows that each PhC binds to the corresponding Fn2 domain, while the two domains are on the same face of the protein. Long timescale explicit solvent molecular dynamics (MD) simulations of PDC109, in the presence and absence of PhC, suggest that PhC binding strongly correlates with the relative orientation of choline-phospholipid binding sites of the two Fn2 domains; unless the two domains tightly bind PhCs, they tend to change their relative orientation by deforming the flexible linker. The effective PDC109-PhC association constant of 28 M(-1), estimated from their potential of mean force is consistent with the experimental result. Principal component analysis of the long timescale MD simulations was compared to the significantly less expensive normal mode analysis of minimized structures. The comparison indicates that difference between relative domain motions of PDC109 with bound and unbound PhC is captured by the first principal component in the principal component analysis as well as the three lowest normal modes in the normal mode analysis. The present study illustrates the use of detailed MD simulations to clarify the energetics of specific ligand-domain interactions revealed by a static crystallographic model, as well as their influence on relative domain motions in a multi-domain protein.

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Snapshots of PDC109 during the MD simulations.Structures of the PDC109-PhC complex at 200 ns (red) and 350 ns (blue) and of ligand-free PDC109 at 350 ns (green) are compared against the X-ray crystallographic structure (yellow) via a best-fit of PDC109/b [74].
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pone-0009180-g008: Snapshots of PDC109 during the MD simulations.Structures of the PDC109-PhC complex at 200 ns (red) and 350 ns (blue) and of ligand-free PDC109 at 350 ns (green) are compared against the X-ray crystallographic structure (yellow) via a best-fit of PDC109/b [74].

Mentions: In the crystal [24], the ligand binding sites of both Fn2 domains position at the same face of the PDC109 molecules but rotated 70 from each other. Fig. 8 compares the X-ray structure (yellow) against snapshots of the PDC109-PhC complex at 200 ns (red) and 350 ns (blue) and against a snapshot of ligand-free PDC109 at 350 ns (green) via a best-fit of the PDC109/b domain (PhC molecules are not shown). Complementing the static X-ray structure, the MD simulations reveal drastic changes in the relative orientations between the two domains at 200 ns for PDC109-PhC and at 350 ns for ligand-free PDC109, respectively. This behavior is rather similar to Fn2 domains oriented in opposite directions and faced 180 from each other in the recently reported structures of human matrix metallo-proteinase 2 (MMP-2) [55], [56]. However, in the presence of PhC, the 350 ns snapshot of PDC109 shows the relative orientation is restored and stabilized close to the X-ray structure, although the linker seems to be more compressed but slightly pushed away from the two domains.


Conformational dynamics and ligand binding in the multi-domain protein PDC109.

Kim HJ, Choi MY, Kim HJ, Llinás M - PLoS ONE (2010)

Snapshots of PDC109 during the MD simulations.Structures of the PDC109-PhC complex at 200 ns (red) and 350 ns (blue) and of ligand-free PDC109 at 350 ns (green) are compared against the X-ray crystallographic structure (yellow) via a best-fit of PDC109/b [74].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2823774&req=5

pone-0009180-g008: Snapshots of PDC109 during the MD simulations.Structures of the PDC109-PhC complex at 200 ns (red) and 350 ns (blue) and of ligand-free PDC109 at 350 ns (green) are compared against the X-ray crystallographic structure (yellow) via a best-fit of PDC109/b [74].
Mentions: In the crystal [24], the ligand binding sites of both Fn2 domains position at the same face of the PDC109 molecules but rotated 70 from each other. Fig. 8 compares the X-ray structure (yellow) against snapshots of the PDC109-PhC complex at 200 ns (red) and 350 ns (blue) and against a snapshot of ligand-free PDC109 at 350 ns (green) via a best-fit of the PDC109/b domain (PhC molecules are not shown). Complementing the static X-ray structure, the MD simulations reveal drastic changes in the relative orientations between the two domains at 200 ns for PDC109-PhC and at 350 ns for ligand-free PDC109, respectively. This behavior is rather similar to Fn2 domains oriented in opposite directions and faced 180 from each other in the recently reported structures of human matrix metallo-proteinase 2 (MMP-2) [55], [56]. However, in the presence of PhC, the 350 ns snapshot of PDC109 shows the relative orientation is restored and stabilized close to the X-ray structure, although the linker seems to be more compressed but slightly pushed away from the two domains.

Bottom Line: The effective PDC109-PhC association constant of 28 M(-1), estimated from their potential of mean force is consistent with the experimental result.Principal component analysis of the long timescale MD simulations was compared to the significantly less expensive normal mode analysis of minimized structures.The present study illustrates the use of detailed MD simulations to clarify the energetics of specific ligand-domain interactions revealed by a static crystallographic model, as well as their influence on relative domain motions in a multi-domain protein.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT
PDC109 is a modular multi-domain protein with two fibronectin type II (Fn2) repeats joined by a linker. It plays a major role in bull sperm binding to the oviductal epithelium through its interactions with phosphorylcholines (PhCs), a head group of sperm cell membrane lipids. The crystal structure of the PDC109-PhC complex shows that each PhC binds to the corresponding Fn2 domain, while the two domains are on the same face of the protein. Long timescale explicit solvent molecular dynamics (MD) simulations of PDC109, in the presence and absence of PhC, suggest that PhC binding strongly correlates with the relative orientation of choline-phospholipid binding sites of the two Fn2 domains; unless the two domains tightly bind PhCs, they tend to change their relative orientation by deforming the flexible linker. The effective PDC109-PhC association constant of 28 M(-1), estimated from their potential of mean force is consistent with the experimental result. Principal component analysis of the long timescale MD simulations was compared to the significantly less expensive normal mode analysis of minimized structures. The comparison indicates that difference between relative domain motions of PDC109 with bound and unbound PhC is captured by the first principal component in the principal component analysis as well as the three lowest normal modes in the normal mode analysis. The present study illustrates the use of detailed MD simulations to clarify the energetics of specific ligand-domain interactions revealed by a static crystallographic model, as well as their influence on relative domain motions in a multi-domain protein.

Show MeSH
Related in: MedlinePlus