Limits...
Building Synthetic Sterols Computationally - Unlocking the Secrets of Evolution?

Róg T, Pöyry S, Vattulainen I - Front Bioeng Biotechnol (2015)

Bottom Line: To this end, we discuss recent atomistic molecular dynamics simulation studies that have predicted new synthetic sterols with properties comparable to those of cholesterol.We also discuss more recent experimental studies that have vindicated these predictions.The paper highlights the strength of computational simulations in making predictions for synthetic biology, thereby guiding experiments.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, Tampere University of Technology , Tampere , Finland.

ABSTRACT
Cholesterol is vital in regulating the physical properties of animal cell membranes. While it remains unclear what renders cholesterol so unique, it is known that other sterols are less capable in modulating membrane properties, and there are membrane proteins whose function is dependent on cholesterol. Practical applications of cholesterol include its use in liposomes in drug delivery and cosmetics, cholesterol-based detergents in membrane protein crystallography, its fluorescent analogs in studies of cholesterol transport in cells and tissues, etc. Clearly, in spite of their difficult synthesis, producing the synthetic analogs of cholesterol is of great commercial and scientific interest. In this article, we discuss how synthetic sterols non-existent in nature can be used to elucidate the roles of cholesterol's structural elements. To this end, we discuss recent atomistic molecular dynamics simulation studies that have predicted new synthetic sterols with properties comparable to those of cholesterol. We also discuss more recent experimental studies that have vindicated these predictions. The paper highlights the strength of computational simulations in making predictions for synthetic biology, thereby guiding experiments.

No MeSH data available.


Sterol–sterol in-plane distribution and configurations of sterol molecules in a DSPC bilayer with 20 mol% sterol. Two-dimensional density distribution for the ring atoms of (A) cholesterol around a tagged cholesterol and (B) Dchol around a tagged Dchol. Both (A,B) show a schematic representation of the tagged sterol (see also Figure 1). The β-face of cholesterol is divided into two sub-faces: β1 and β2. (A) shows that cholesterols avoid the first coordination shell, instead forming a clear second coordination shell. The three emerging peaks, each on a different face, are marked with blue arrows. (B) shows that the two sides of Dchol behave in a similar manner as the smooth α-face of cholesterol. No Dchol is seen in the first coordination shell, and peaks (marked with blue arrows) are observed on both faces. Some structure is still visible in the outer coordination shell around 1.8 nm. Two peaks, which are collinear with the previous ones, are marked with green arrows. This reflects a strong preference to form linear Dchol–Dchol structures. (C,D) show a top view of an equilibrated configuration of (C) a DSPC/cholesterol bilayer and (D) a DSPC/Dchol bilayer. Only one leaflet is drawn for clarity. PC molecules are shown as black sticks and sterols with a red space-filling model. The boundary of the simulation box is marked with the green square and color brightness. (C) shows the connections between neighboring cholesterol molecules forming triangular patterns, whereas in (D), the connection patterns formed by Dchol molecules are clearly linear. This fundamental difference is due to the missing out-of-plane methyl groups in the Dchol molecule. Figure adapted from Martinez-Seara et al. (2010).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4543873&req=5

Figure 2: Sterol–sterol in-plane distribution and configurations of sterol molecules in a DSPC bilayer with 20 mol% sterol. Two-dimensional density distribution for the ring atoms of (A) cholesterol around a tagged cholesterol and (B) Dchol around a tagged Dchol. Both (A,B) show a schematic representation of the tagged sterol (see also Figure 1). The β-face of cholesterol is divided into two sub-faces: β1 and β2. (A) shows that cholesterols avoid the first coordination shell, instead forming a clear second coordination shell. The three emerging peaks, each on a different face, are marked with blue arrows. (B) shows that the two sides of Dchol behave in a similar manner as the smooth α-face of cholesterol. No Dchol is seen in the first coordination shell, and peaks (marked with blue arrows) are observed on both faces. Some structure is still visible in the outer coordination shell around 1.8 nm. Two peaks, which are collinear with the previous ones, are marked with green arrows. This reflects a strong preference to form linear Dchol–Dchol structures. (C,D) show a top view of an equilibrated configuration of (C) a DSPC/cholesterol bilayer and (D) a DSPC/Dchol bilayer. Only one leaflet is drawn for clarity. PC molecules are shown as black sticks and sterols with a red space-filling model. The boundary of the simulation box is marked with the green square and color brightness. (C) shows the connections between neighboring cholesterol molecules forming triangular patterns, whereas in (D), the connection patterns formed by Dchol molecules are clearly linear. This fundamental difference is due to the missing out-of-plane methyl groups in the Dchol molecule. Figure adapted from Martinez-Seara et al. (2010).

Mentions: Another difference between cholesterol and Dchol can be easily visualized. If we look at the cholesterol molecule perpendicularly from its side (Figure 1), we see a clear pattern – a flat and a rough face. Now, if we instead look at the cholesterol molecule from top down, we see a kind of threefold symmetry, shown in Figures 1 and 2. This is caused by the β-face being subdivided into two further faces (Martinez-Seara et al., 2010). Dchol, due to its lack of methyl groups on the β-face, does not display this kind of threefold symmetry. The difference can be visualized well by looking at the two-dimensional radial distribution of cholesterols around a tagged cholesterol shown in Figure 2. This difference may affect the phase behavior of lipid bilayers. As we mentioned above, lanosterol does not promote the Lo phase formation, and due to the additional methyl group does not possess the threefold symmetry. As depicted in Figure 2, our preliminary data suggest that the symmetry of cholesterol’s ring affects the sterol–sterol arrangement. Sterols tend to locate in the second coordination shell of each other, with a lipid molecule in between (Martinez-Seara et al., 2010). Due to the threefold symmetry, cholesterol molecules are able to form a fork net (Figure 2) that is likely capable of covering large areas. By contrast, Dchol has only twofold symmetry and thus forms linear structures. It seems plausible that this different form of molecular packing will affect also the phase behavior of Dchol. At this point, we need more extensive studies to further clarify the matter.


Building Synthetic Sterols Computationally - Unlocking the Secrets of Evolution?

Róg T, Pöyry S, Vattulainen I - Front Bioeng Biotechnol (2015)

Sterol–sterol in-plane distribution and configurations of sterol molecules in a DSPC bilayer with 20 mol% sterol. Two-dimensional density distribution for the ring atoms of (A) cholesterol around a tagged cholesterol and (B) Dchol around a tagged Dchol. Both (A,B) show a schematic representation of the tagged sterol (see also Figure 1). The β-face of cholesterol is divided into two sub-faces: β1 and β2. (A) shows that cholesterols avoid the first coordination shell, instead forming a clear second coordination shell. The three emerging peaks, each on a different face, are marked with blue arrows. (B) shows that the two sides of Dchol behave in a similar manner as the smooth α-face of cholesterol. No Dchol is seen in the first coordination shell, and peaks (marked with blue arrows) are observed on both faces. Some structure is still visible in the outer coordination shell around 1.8 nm. Two peaks, which are collinear with the previous ones, are marked with green arrows. This reflects a strong preference to form linear Dchol–Dchol structures. (C,D) show a top view of an equilibrated configuration of (C) a DSPC/cholesterol bilayer and (D) a DSPC/Dchol bilayer. Only one leaflet is drawn for clarity. PC molecules are shown as black sticks and sterols with a red space-filling model. The boundary of the simulation box is marked with the green square and color brightness. (C) shows the connections between neighboring cholesterol molecules forming triangular patterns, whereas in (D), the connection patterns formed by Dchol molecules are clearly linear. This fundamental difference is due to the missing out-of-plane methyl groups in the Dchol molecule. Figure adapted from Martinez-Seara et al. (2010).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4543873&req=5

Figure 2: Sterol–sterol in-plane distribution and configurations of sterol molecules in a DSPC bilayer with 20 mol% sterol. Two-dimensional density distribution for the ring atoms of (A) cholesterol around a tagged cholesterol and (B) Dchol around a tagged Dchol. Both (A,B) show a schematic representation of the tagged sterol (see also Figure 1). The β-face of cholesterol is divided into two sub-faces: β1 and β2. (A) shows that cholesterols avoid the first coordination shell, instead forming a clear second coordination shell. The three emerging peaks, each on a different face, are marked with blue arrows. (B) shows that the two sides of Dchol behave in a similar manner as the smooth α-face of cholesterol. No Dchol is seen in the first coordination shell, and peaks (marked with blue arrows) are observed on both faces. Some structure is still visible in the outer coordination shell around 1.8 nm. Two peaks, which are collinear with the previous ones, are marked with green arrows. This reflects a strong preference to form linear Dchol–Dchol structures. (C,D) show a top view of an equilibrated configuration of (C) a DSPC/cholesterol bilayer and (D) a DSPC/Dchol bilayer. Only one leaflet is drawn for clarity. PC molecules are shown as black sticks and sterols with a red space-filling model. The boundary of the simulation box is marked with the green square and color brightness. (C) shows the connections between neighboring cholesterol molecules forming triangular patterns, whereas in (D), the connection patterns formed by Dchol molecules are clearly linear. This fundamental difference is due to the missing out-of-plane methyl groups in the Dchol molecule. Figure adapted from Martinez-Seara et al. (2010).
Mentions: Another difference between cholesterol and Dchol can be easily visualized. If we look at the cholesterol molecule perpendicularly from its side (Figure 1), we see a clear pattern – a flat and a rough face. Now, if we instead look at the cholesterol molecule from top down, we see a kind of threefold symmetry, shown in Figures 1 and 2. This is caused by the β-face being subdivided into two further faces (Martinez-Seara et al., 2010). Dchol, due to its lack of methyl groups on the β-face, does not display this kind of threefold symmetry. The difference can be visualized well by looking at the two-dimensional radial distribution of cholesterols around a tagged cholesterol shown in Figure 2. This difference may affect the phase behavior of lipid bilayers. As we mentioned above, lanosterol does not promote the Lo phase formation, and due to the additional methyl group does not possess the threefold symmetry. As depicted in Figure 2, our preliminary data suggest that the symmetry of cholesterol’s ring affects the sterol–sterol arrangement. Sterols tend to locate in the second coordination shell of each other, with a lipid molecule in between (Martinez-Seara et al., 2010). Due to the threefold symmetry, cholesterol molecules are able to form a fork net (Figure 2) that is likely capable of covering large areas. By contrast, Dchol has only twofold symmetry and thus forms linear structures. It seems plausible that this different form of molecular packing will affect also the phase behavior of Dchol. At this point, we need more extensive studies to further clarify the matter.

Bottom Line: To this end, we discuss recent atomistic molecular dynamics simulation studies that have predicted new synthetic sterols with properties comparable to those of cholesterol.We also discuss more recent experimental studies that have vindicated these predictions.The paper highlights the strength of computational simulations in making predictions for synthetic biology, thereby guiding experiments.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, Tampere University of Technology , Tampere , Finland.

ABSTRACT
Cholesterol is vital in regulating the physical properties of animal cell membranes. While it remains unclear what renders cholesterol so unique, it is known that other sterols are less capable in modulating membrane properties, and there are membrane proteins whose function is dependent on cholesterol. Practical applications of cholesterol include its use in liposomes in drug delivery and cosmetics, cholesterol-based detergents in membrane protein crystallography, its fluorescent analogs in studies of cholesterol transport in cells and tissues, etc. Clearly, in spite of their difficult synthesis, producing the synthetic analogs of cholesterol is of great commercial and scientific interest. In this article, we discuss how synthetic sterols non-existent in nature can be used to elucidate the roles of cholesterol's structural elements. To this end, we discuss recent atomistic molecular dynamics simulation studies that have predicted new synthetic sterols with properties comparable to those of cholesterol. We also discuss more recent experimental studies that have vindicated these predictions. The paper highlights the strength of computational simulations in making predictions for synthetic biology, thereby guiding experiments.

No MeSH data available.