unsaturation is larger. Assuming that an increase in width of the
distribution linearly decreases the free energy of activation, the
$un_f$ parameter must follow
-$x^{\mathrm{stdev}\left(un_\mathrm{ves}\right)}$ where $x > 1$, so a
-convenient starting base for $x$ is 2:
+$a^{\mathrm{stdev}\left(un_\mathrm{ves}\right)}$ where $a > 1$, so a
+convenient starting base for $a$ is $2$:
\begin{equation}
un_f = 2^{\mathrm{stdev}\left(un_\mathrm{ves}\right)}
\label{eq:unsaturation_forward}
\end{equation}
+The most common $\mathrm{stdev}\left(un_\mathrm{ves}\right)$ is around
+$1.5$, which leads to a $\Delta \Delta G^\ddagger$ of
+$\Sexpr{format(digits=3,to.kcal(2^1.5))}
+\frac{\mathrm{kcal}}{\mathrm{mol}}$.
+
+It is not clear that the unsaturation of the inserted monomer will
+affect the rate of the insertion positively or negatively, so we do
+not include a term for it in this formalism.
+
+
\setkeys{Gin}{width=3.2in}
<<fig=TRUE,echo=FALSE,results=hide,width=5,height=5>>=
curve(2^x,from=0,to=sd(c(0,4)),
dependent upon the charge of the monomer and the average charge of the
vesicle. If either the vesicle or the monomer has no charge, there
should be no effect of charge upon the rate. This leads us to the
-following equation, $x^{-\left<ch_v\right> ch_m}$, where
+following equation, $a^{-\left<ch_v\right> ch_m}$, where
$\left<ch_v\right>$ is the average charge of the vesicle, and $ch_m$
is the charge of the monomer. If either $\left<ch_v\right>$ or $ch_m$
is 0, the adjustment parameter is 1 (no change), whereas it decreases
if both are positive or negative, as the product of two real numbers
-with the same sign is always positive. A convenient base for $x$ is
+with the same sign is always positive. A convenient base for $a$ is
60, resulting in the following equation:
\label{eq:charge_forward}
\end{equation}
+The most common $\left<{ch}_v\right>$ is around $-0.165$, which leads to
+a range of $\Delta \Delta G^\ddagger$ from
+$\Sexpr{format(digits=3,to.kcal(60^(-.165*-1)))}
+\frac{\mathrm{kcal}}{\mathrm{mol}}$ to $0\frac{\mathrm{kcal}}{\mathrm{mol}}$.
+
<<fig=TRUE,echo=FALSE,results=hide,width=7,height=7>>=
x <- seq(-1,0,length.out=20)
y <- seq(-1,0,length.out=20)
As in the case of unsaturation, void formation is increased by the
presence of lipids with mismatched curvature. Thus, a larger
distribution of curvature in the vesicle increases the rate of lipid
-insertion into the vesicle. However, a species with curvature $e^-1$
+insertion into the vesicle. However, a species with curvature $e^{-1}$
will cancel out a species with curvature $e$, so we have to log
transform (turning these into -1 and 1), then take the absolute value
(1 and 1), and finally measure the width of the distribution. Thus, by
using the log transform to make the range of the lipid curvature equal
-between positive and negative, taking the absolute value to cancel out
+between positive and negative, and taking the average to cancel out
exactly mismatched curvatures, we come to an equation with the shape
-$x^{\mathrm{stdev}\left|\log cu_\mathrm{vesicle}\right|}$, and a
-convenient base for $x$ is 10, yielding:
-
-{\color{red} Shouldn't a vesicle of -1,1,0 have the same activation
- energy as a vesicle of 0,0,0? It doesn't currently.}
+$a^{\left<\log cu_\mathrm{vesicle}\right>}$. A convenient base for $a$
+is $10$, yielding:
\begin{equation}
- cu_f = 10^{\mathrm{stdev}\left|\log cu_\mathrm{vesicle}\right|}
+ % cu_f = 10^{\mathrm{stdev}\left|\log cu_\mathrm{vesicle}\right|}
+ cu_f = 10^{\left|\left<\log cu_\mathrm{vesicle} \right>\right|\mathrm{stdev} \left|\log cu_\mathrm{vesicle}\right|}
\label{eq:curvature_forward}
\end{equation}
+The most common $\left|\left<\log {cu}_v\right>\right|$ is around
+$0.013$, which with the most common $\mathrm{stdev} \log
+cu_\mathrm{vesicle}$ of $0.213$ leads to a $\Delta \Delta G^\ddagger$
+of $\Sexpr{format(digits=3,to.kcal(10^(0.13*0.213)))}
+\frac{\mathrm{kcal}}{\mathrm{mol}}$. This is a consequence of the
+relatively matched curvatures in our environment.
-<<fig=TRUE,echo=FALSE,results=hide,width=7,height=5>>=
-curve(10^x,from=0,to=max(c(sd(abs(log(c(0.8,1.33)))),
- sd(abs(log(c(1,1.33)))),
- sd(abs(log(c(0.8,1)))))),
- main="Curvature forward",
- xlab="Standard Deviation of Absolute value of the Log of the Curvature of Vesicle",
- ylab="Curvature Forward Adjustment")
+% 1.5 to 0.75 3 to 0.33
+<<fig=TRUE,echo=FALSE,results=hide,width=7,height=7>>=
+grid <- expand.grid(x=seq(0,max(c(sd(abs(log(c(1,3)))),
+ sd(abs(log(c(1,0.33)))),sd(abs(log(c(0.33,3)))))),length.out=20),
+ y=seq(0,max(c(mean(log(c(1,3)),
+ mean(log(c(1,0.33))),
+ mean(log(c(0.33,3)))))),length.out=20))
+grid$z <- 10^(grid$x*grid$y)
+print(wireframe(z~x*y,grid,cuts=50,
+ drape=TRUE,
+ scales=list(arrows=FALSE),
+ xlab=list("Vesicle stdev log curvature",rot=30),
+ ylab=list("Vesicle average log curvature",rot=-35),
+ zlab=list("Vesicle Curvature Forward",rot=93)))
+rm(grid)
@
-<<fig=TRUE,echo=FALSE,results=hide,width=7,height=5>>=
-curve(to.kcal(10^x),from=0,to=max(c(sd(abs(log(c(0.8,1.33)))),
- sd(abs(log(c(1,1.33)))),
- sd(abs(log(c(0.8,1)))))),
- main="Curvature forward",
- xlab="Standard Deviation of Absolute value of the Log of the Curvature of Vesicle",
- ylab="Curvature Forward Adjustment (kcal/mol)")
+<<fig=TRUE,echo=FALSE,results=hide,width=7,height=7>>=
+grid <- expand.grid(x=seq(0,max(c(sd(abs(log(c(1,3)))),
+ sd(abs(log(c(1,0.33)))),sd(abs(log(c(0.33,3)))))),length.out=20),
+ y=seq(0,max(c(mean(log(c(1,3)),
+ mean(log(c(1,0.33))),
+ mean(log(c(0.33,3)))))),length.out=20))
+grid$z <- to.kcal(10^(grid$x*grid$y))
+print(wireframe(z~x*y,grid,cuts=50,
+ drape=TRUE,
+ scales=list(arrows=FALSE),
+ xlab=list("Vesicle stdev log curvature",rot=30),
+ ylab=list("Vesicle average log curvature",rot=-35),
+ zlab=list("Vesicle Curvature Forward (kcal/mol)",rot=93)))
+rm(grid)
@
-
\newpage
\subsubsection{Length Forward}
\label{eq:length_forward}
\end{equation}
+The most common $\mathrm{stdev} l_\mathrm{ves}$ is around $3.4$, which leads to
+a range of $\Delta \Delta G^\ddagger$ of
+$\Sexpr{format(digits=3,to.kcal(2^(3.4)))}
+\frac{\mathrm{kcal}}{\mathrm{mol}}$.
+
+While it could be argued that increased length of the monomer could
+affect the rate of insertion into the membrane, it's not clear whether
+it would increase (by decreasing the number of available hydrogen
+bonds, for example) or decrease (by increasing the time taken to fully
+insert the acyl chain, for example) the rate of insertion or to what
+degree, so we do not take it into account in this formalism.
+
+
<<fig=TRUE,echo=FALSE,results=hide,width=7,height=5>>=
curve(2^x,from=0,to=sd(c(12,24)),
main="Length forward",
a membrane. If a molecule has an unsaturation level which is different
from the surrounding membrane, it will be more likely to leave the
membrane. The more different the unsaturation level is, the greater
-the propensity for the lipid molecule to leave. Therefore, an equation
-with the shape
-$x^{\left|y^{-\left<un_\mathrm{ves}\right>}-y^{-un_\mathrm{monomer}}\right|}$
+the propensity for the lipid molecule to leave. However, a vesicle
+with some unsaturation is more favorable for lipids with more
+unsaturation than the equivalent amount of less unsatuturation, so the
+difference in energy between unsaturation is not linear. Therefore, an
+equation with the shape
+$x^{\left| y^{-\left< un_\mathrm{ves}\right> }-y^{-un_\mathrm{monomer}} \right| }$
where $\left<un_\mathrm{ves}\right>$ is the average unsaturation of
the vesicle, and $un_\mathrm{monomer}$ is the average unsaturation. In
-this equation, as the average unsaturation of the vesicle is larger,
+this equation, as the average unsaturation of the vesicle is larger,
\begin{equation}
- un_b = 10^{\left|3.5^{-\left<un_\mathrm{ves}\right>}-3.5^{-un_\mathrm{monomer}}\right|}
+ un_b = 7^{1-\left(20\left(2^{-\left<un_\mathrm{vesicle} \right>} - 2^{-un_\mathrm{monomer}} \right)^2+1\right)^{-1}}
\label{eq:unsaturation_backward}
\end{equation}
+The most common $\left<un_\mathrm{ves}\right>$ is around $1.7$, which leads to
+a range of $\Delta \Delta G^\ddagger$ from
+$\Sexpr{format(digits=3,to.kcal(7^(1-1/(5*(2^-1.7-2^-0)^2+1))))}
+\frac{\mathrm{kcal}}{\mathrm{mol}}$ for monomers with 0 unsaturation
+to
+$\Sexpr{format(digits=3,to.kcal(7^(1-1/(5*(2^-1.7-2^-4)^2+1))))}\frac{\mathrm{kcal}}{\mathrm{mol}}$
+for monomers with 4 unsaturations.
+
+
<<fig=TRUE,echo=FALSE,results=hide,width=7,height=7>>=
grid <- expand.grid(x=seq(0,4,length.out=20),
y=seq(0,4,length.out=20))
-grid$z <- 10^(abs(3.5^-grid$x-3.5^-grid$y))
+grid$z <- (7^(1-1/(5*(2^-grid$x-2^-grid$y)^2+1)))
print(wireframe(z~x*y,grid,cuts=50,
drape=TRUE,
scales=list(arrows=FALSE),
<<fig=TRUE,echo=FALSE,results=hide,width=7,height=7>>=
grid <- expand.grid(x=seq(0,4,length.out=20),
y=seq(0,4,length.out=20))
-grid$z <- to.kcal(10^(abs(3.5^-grid$x-3.5^-grid$y)))
+grid$z <- to.kcal((7^(1-1/(5*(2^-grid$x-2^-grid$y)^2+1))))
print(wireframe(z~x*y,grid,cuts=50,
drape=TRUE,
scales=list(arrows=FALSE),
@
+
\newpage
\subsubsection{Charge Backwards}
+As in the case of monomers entering a vesicle, monomers leaving a
+vesicle leave faster if their charge has the same sign as the average
+charge vesicle. An equation of the form $ch_b = a^{\left<ch_v\right>
+ ch_m}$ is then appropriate, and using a base of $a=20$ yields:
+
\begin{equation}
ch_b = 20^{\left<{ch}_v\right> {ch}_m}
\label{eq:charge_backwards}
\end{equation}
+The most common $\left<ch_v\right>$ is around $-0.164$, which leads to
+a range of $\Delta \Delta G^\ddagger$ from
+$\Sexpr{format(digits=3,to.kcal(20^(-.164*-1)))}
+\frac{\mathrm{kcal}}{\mathrm{mol}}$ for monomers with charge $-1$ to
+$0\frac{\mathrm{kcal}}{\mathrm{mol}}$
+for monomers with charge $0$.
+
+
<<fig=TRUE,echo=FALSE,results=hide,width=7,height=7>>=
x <- seq(-1,0,length.out=20)
y <- seq(-1,0,length.out=20)
\newpage
\subsubsection{Curvature Backwards}
+
+The less a monomer's intrinsic curvature matches the average curvature
+of the vesicle in which it is in, the greater its rate of efflux. If
+the difference is 0, $cu_f$ needs to be one. To map negative and
+positive curvature to the same range, we also need take the logarithm.
+Increasing mismatches in curvature increase the rate of efflux, but
+asymptotically. An equation which satisfies this critera has the
+form $cu_f = a^{1-\left(b\left( \left< \log cu_\mathrm{vesicle} \right>
+ -\log cu_\mathrm{monomer}\right)^2+1\right)^{-1}}$. An
+alternative form would use the aboslute value of the difference,
+however, this yields a cusp and sharp increase about the curvature
+equilibrium, which is decidedly non-elegant. We have chosen bases of
+$a=7$ and $b=20$.
+
\begin{equation}
- cu_f = 7^{1-\left(20\left(\log_{e} cu_\mathrm{vesicle}-\log_{e} cu_\mathrm{monomer}\right)^2+1\right)^{-1}}
+ cu_b = 7^{1-\left(20\left(\left< \log cu_\mathrm{vesicle} \right> -\log cu_\mathrm{monomer} \right)^2+1\right)^{-1}}
\label{eq:curvature_backwards}
\end{equation}
+The most common $\left<\log cu_\mathrm{ves}\right>$ is around $-0.013$, which leads to
+a range of $\Delta \Delta G^\ddagger$ from
+$\Sexpr{format(digits=3,to.kcal(7^(1-1/(20*(-0.013-log(0.8))^2+1))))}
+\frac{\mathrm{kcal}}{\mathrm{mol}}$ for monomers with curvature 0.8
+to
+$\Sexpr{format(digits=3,to.kcal(7^(1-1/(20*(-0.013-log(1.3))^2+1))))}\frac{\mathrm{kcal}}{\mathrm{mol}}$
+for monomers with curvature 1.3 to $0\frac{\mathrm{kcal}}{\mathrm{mol}}$ for monomers with curvature near 1.
+
+
<<fig=TRUE,echo=FALSE,results=hide,width=7,height=7>>=
grid <- expand.grid(x=seq(0.8,1.33,length.out=20),
y=seq(0.8,1.33,length.out=20))
rm(grid)
@
-
\newpage
\subsubsection{Length Backwards}
+
+In a model membrane, the dissociation constant increases by a factor
+of approximately 3.2 per carbon decrease in acyl chain length (Nichols
+1985). Unfortunatly, the experimental data known to us only measures
+chain length less than or equal to the bulk lipid, and does not exceed
+it, and is only known for one bulk lipid species (DOPC). We assume
+then, that the increase is in relationship to the average vesicle, and
+that lipids with larger acyl chain length will also show an increase
+in their dissociation constant.
+
\begin{equation}
- l_b = 3.2^{\left|l_\mathrm{ves}-l_\mathrm{monomer}\right|}
+ l_b = 3.2^{\left|\left<l_\mathrm{ves}\right>-l_\mathrm{monomer}\right|}
\label{eq:length_backward}
\end{equation}
+The most common $\left<\log l_\mathrm{ves}\right>$ is around $17.75$, which leads to
+a range of $\Delta \Delta G^\ddagger$ from
+$\Sexpr{format(digits=3,to.kcal(3.2^abs(12-17.75)))}
+\frac{\mathrm{kcal}}{\mathrm{mol}}$ for monomers with length 12
+to
+$\Sexpr{format(digits=3,to.kcal(3.2^abs(24-17.75)))}\frac{\mathrm{kcal}}{\mathrm{mol}}$
+for monomers with length 24 to $0\frac{\mathrm{kcal}}{\mathrm{mol}}$ for monomers with curvature near 18.
+
+
<<fig=TRUE,echo=FALSE,results=hide,width=7,height=7>>=
grid <- expand.grid(x=seq(12,24,length.out=20),
y=seq(12,24,length.out=20))
\newpage
\subsubsection{Complex Formation Backward}
+
+Complex formation describes the interaction between CHOL and PC or SM,
+where PC or SM protects the hydroxyl group of CHOL from interactions
+with water, the ``Umbrella Model''. PC ($CF1=2$) can interact with two
+CHOL, and SM ($CF1=3$) with three CHOL ($CF1=-1$). If the average of
+$CF1$ is positive (excess of SM and PC with regards to complex
+formation), species with negative $CF1$ (CHOL) will be retained. If
+average $CF1$ is negative, species with positive $CF1$ are retained.
+An equation which has this property is
+$CF1_b=a^{\left<CF1_\mathrm{ves}\right>
+ CF1_\mathrm{monomer}-\left|\left<CF1_\mathrm{ves}\right>
+ CF1_\mathrm{monomer}\right|}$, where difference of the exponent is
+zero if the average $CF1$ and the $CF1$ of the specie have the same
+sign, or double the product if the signs are different. A convenient
+base for $a$ is $1.5$.
+
+
\begin{equation}
- CF1_b=1.5^{CF1_\mathrm{ves} CF1_\mathrm{monomer}-\left|CF1_\mathrm{ves} CF1_\mathrm{monomer}\right|}
+ CF1_b=1.5^{\left<CF1_\mathrm{ves}\right> CF1_\mathrm{monomer}-\left|\left<CF1_\mathrm{ves}\right> CF1_\mathrm{monomer}\right|}
\label{eq:complex_formation_backward}
\end{equation}
+The most common $\left<CF1_\mathrm{ves}\right>$ is around $0.925$,
+which leads to a range of $\Delta \Delta G^\ddagger$ from
+$\Sexpr{format(digits=3,to.kcal(1.5^(0.925*-1-abs(0.925*-1))))}
+\frac{\mathrm{kcal}}{\mathrm{mol}}$ for monomers with complex
+formation $-1$ to
+$\Sexpr{format(digits=3,to.kcal(1.5^(0.925*2-abs(0.925*2))))}\frac{\mathrm{kcal}}{\mathrm{mol}}$
+for monomers with complex formation $2$ to
+$0\frac{\mathrm{kcal}}{\mathrm{mol}}$ for monomers with complex
+formation $0$.
+
+
<<fig=TRUE,echo=FALSE,results=hide,width=7,height=7>>=
grid <- expand.grid(x=seq(-1,3,length.out=20),
y=seq(-1,3,length.out=20))
-grid$z <- 3.2^(grid$x*grid$y-abs(grid$x*grid$y))
+grid$z <- 1.5^(grid$x*grid$y-abs(grid$x*grid$y))
print(wireframe(z~x*y,grid,cuts=50,
drape=TRUE,
scales=list(arrows=FALSE),
<<fig=TRUE,echo=FALSE,results=hide,width=7,height=7>>=
grid <- expand.grid(x=seq(-1,3,length.out=20),
y=seq(-1,3,length.out=20))
-grid$z <- to.kcal(3.2^(grid$x*grid$y-abs(grid$x*grid$y)))
+grid$z <- to.kcal(1.5^(grid$x*grid$y-abs(grid$x*grid$y)))
print(wireframe(z~x*y,grid,cuts=50,
drape=TRUE,
scales=list(arrows=FALSE),
projects / ool / lipid_simulation_formalism.git / blobdiff