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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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Potentials of mean force (PMFs) between PhC and the individual PDC109 domains.PMFs for PDC109/a (A) and PDC109/b (B) are displayed with standard deviations every 10 points. The insets display histogram of the number of sampling points with respect to the distance coordinate (scaled by 10).
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pone-0009180-g005: Potentials of mean force (PMFs) between PhC and the individual PDC109 domains.PMFs for PDC109/a (A) and PDC109/b (B) are displayed with standard deviations every 10 points. The insets display histogram of the number of sampling points with respect to the distance coordinate (scaled by 10).

Mentions: We have examined binding affinities of PhC to the PDC109 binding sites using potential of mean force (PMF) calculations. For simplicity, the distance between centers of mass of binding site atoms in a PDC109 domain and the corresponding PhC was chosen as reaction coordinate . It should be noted that a reaction coordinate similar to ours is widely employed in theoretical analysis of many dissociation and association reactions in condensed phases [52]. The PMF profiles for PDC109/a-PhC and PDC109/b-PhC are displayed with their standard deviations in Fig. 5 A and B, respectively. For both domains, the PMF along shows two local minima. In the PDC109/a-PhC case, they are located around Å and 5.6 Å with respective well depths 1.0 kcal/mol and 2.1 kcal/mol. The position and well depth of the corresponding minima for PDC109/b-PhC are 3.0 Å and 1.1 kcal/mol and 5.7 Å and 2.0 kcal/mol. In either case, the local minimum at the larger is the global minimum. The estimated errors (see Eq. 3 below) are less than 1.0 kcal/mol in all but one window with 6 Å Å. In addition, Fig. 6 A and B illustrate the PMFs for PDC109/a-PhC and PDC109/b-PhC including their profiles in the overlapping regions between neighboring windows, respectively. The PMF profiles in these regions further support accuracy of the PMF calculations.


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

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

Potentials of mean force (PMFs) between PhC and the individual PDC109 domains.PMFs for PDC109/a (A) and PDC109/b (B) are displayed with standard deviations every 10 points. The insets display histogram of the number of sampling points with respect to the distance coordinate (scaled by 10).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0009180-g005: Potentials of mean force (PMFs) between PhC and the individual PDC109 domains.PMFs for PDC109/a (A) and PDC109/b (B) are displayed with standard deviations every 10 points. The insets display histogram of the number of sampling points with respect to the distance coordinate (scaled by 10).
Mentions: We have examined binding affinities of PhC to the PDC109 binding sites using potential of mean force (PMF) calculations. For simplicity, the distance between centers of mass of binding site atoms in a PDC109 domain and the corresponding PhC was chosen as reaction coordinate . It should be noted that a reaction coordinate similar to ours is widely employed in theoretical analysis of many dissociation and association reactions in condensed phases [52]. The PMF profiles for PDC109/a-PhC and PDC109/b-PhC are displayed with their standard deviations in Fig. 5 A and B, respectively. For both domains, the PMF along shows two local minima. In the PDC109/a-PhC case, they are located around Å and 5.6 Å with respective well depths 1.0 kcal/mol and 2.1 kcal/mol. The position and well depth of the corresponding minima for PDC109/b-PhC are 3.0 Å and 1.1 kcal/mol and 5.7 Å and 2.0 kcal/mol. In either case, the local minimum at the larger is the global minimum. The estimated errors (see Eq. 3 below) are less than 1.0 kcal/mol in all but one window with 6 Å Å. In addition, Fig. 6 A and B illustrate the PMFs for PDC109/a-PhC and PDC109/b-PhC including their profiles in the overlapping regions between neighboring windows, respectively. The PMF profiles in these regions further support accuracy of the PMF calculations.

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