differences, producing excellent statistics for the mean, but making
it difficult to understand the variation. The individualized, and
sometimes rare, behaviors of macromolecules can have important
-implications for their functions inside the cell. For example,
-...\citep{TODO}. Single molecule techniques, in which the
-macromolecules are studied one at a time, allow direct access to the
-variation within the population without averaging. This provides
-important and complementary information about the functional
-mechanisms of several biological systems\citep{bustamante08}.
+implications for their functions inside the cell. Single molecule
+techniques, in which the macromolecules are studied one at a time,
+allow direct access to the variation within the population without
+averaging. This provides important and complementary information
+about the functional mechanisms of several biological
+systems\citep{betterment08}.
% What do genes do? Why is protein folding interesting?
-
+An organism's genetic code is stored in DNA in the cell nucleus.
DNA sequencing is a fairly well developed field, with fundamental work
such as the Human Genome Project seeing major development in the early
2000s\citep{wolfsberg01,mcpherson01,collins03}. It is estimated that
-this genetic information contains approximately 25,000 genes, each
+human genetic information contains approximately 25,000 genes, each
encoding a protein\citep{claverie01,venter01}. Knowing the amino acid
sequence for a particular protein, however, does not immediately shed
light on the protein's role in the body, or even the protein's
probable conformation. Indeed, a protein's conformation is often
vitally important in executing its biological tasks
-(\cref{fig:ligand-receptor}). Unfortunately predicting stable
-conformations of a given amino acid sequence, and the inverse problem
-of finding sequences that form a given conformation, have proven
-remarkably difficult problems.
+(\cref{fig:ligand-receptor}). Unfortunately both predicting stable
+conformations of a given amino acid sequence and the inverse problem
+of finding sequences that form a given conformation have proven
+remarkably difficult.
\begin{figure}
\begin{center}
\end{center}
\end{figure}
-As pointed out by \citet{levinthal69}, folding
-a protein via a brute force sampling of all possible conformations
-is impossibly inefficient, due to the huge size
-
+% the free energy landscape
-
-There has been a wealth of
-information on the genetic code
+Folding a protein via a brute force sampling of all possible
+conformations is impossibly inefficient, due to the exponential
+scaling of possible conformations with protein length, as outlined by
+\citet{levinthal69}. This has lead to a succession of models
+explaining the folding mechanism. For a number of years, the
+``pathway'' model of protein folding enjoyed popularity
+(\cref{fig:folding:pathway})\citep{levinthal69}. More recently, the
+``landscape'' or ``funnel'' model has come to the fore
+(\cref{fig:folding:landscape})\citep{dill97}.
-% Protein folding / unfolding
-
-One particularly interesting area of biophysics is protein folding.
-Proteins are chains of amino acids, and from \emph{central dogma} of
-molecular biology, DNA specifies the amino acid sequence
-exactly\citep{TODO}. It is cur
+\begin{figure}
+ \begin{center}
+ \subfloat[][]{\includegraphics[width=2in]{figures/schematic/pathway}%
+ \label{fig:folding:pathway}}
+ % \hspace{.25in}%
+ \subfloat[][]{\includegraphics[width=2in]{figures/schematic/dill97-fig4}%
+ \label{fig:folding:landscape}}
+ \caption{(a) The pathway model of protein folding, in which the
+ protein proceeds through a well defined series of metastable
+ transition states. Reproduced from \citet{TODO}. (b) The landscape
+ model of protein folding, in which the protein diffuses through a
+ multi-dimensional free energy landscape. Separate folding
+ attempts may take many distinct routes through this landscape on
+ the way to the folded state. Reproduced from \citet{dill97}.
+ \label{fig:folding}}
+ \end{center}
+\end{figure}
+What drives the initial folding? \citet{levinthal68} proposed
+a model based on secondary structure nucleation, but recent work has
+focused on early hydrophobic collapse\citep{TODO}.
% why AFM & what an AFM is
Single molecule techniques for the study of biological macromolecules
@String{NAT = "Nature"}
@String{NSB = "Nat. Struct. Biol."}
%String{NSB = "Nature Structural Biology"}
+@String{NSMB = "Nat. Struct. Mol. Biol."}
+%String{NSMB = "Nature Structural Molecular Biology"}
@String{NAR = "Nucleic Acids Res."}
%String{NAR = "Nucleic Acids Research"}
@String{PRL = "Phys. Rev. Lett."}
}
-@Article{Schwaiger04,
+@Article{schwaiger04,
author = "Ingo Schwaiger and Angelika Kardinal and Michael
Schleicher and Angelika A. Noegel and "# MRief,
title = "A mechanical unfolding intermediate in an
actin-crosslinking protein",
- journal = "Nat Struct Mol Biol",
- year = "2004",
+ journal = NSMB,
+ year = 2004,
month = jan,
- day = "29",
- volume = "11",
- number = "1",
+ day = 29,
+ volume = 11,
+ number = 1,
pages = "81--85",
keywords = "Actins",
keywords = "Animals",
url = "http://www.sciencedirect.com/science/article/B6WBK-4F5M7K3-3C/2/c94b612e06efc8534ee24bb1da889811",
note = "Biological role of streptavidin.",
}
+
+@Article{dill97,
+ author = "K. A. Dill and H. S. Chan",
+ title = "From Levinthal to pathways to funnels.",
+ journal = NSB,
+ year = 1997,
+ month = jan,
+ volume = 4,
+ number = 1,
+ pages = "10--19",
+ keywords = "Kinetics",
+ keywords = "Models, Chemical",
+ keywords = "Protein Folding",
+ abstract = "While the classical view of protein folding kinetics
+ relies on phenomenological models, and regards folding
+ intermediates in a structural way, the new view
+ emphasizes the ensemble nature of protein
+ conformations. Although folding has sometimes been
+ regarded as a linear sequence of events, the new view
+ sees folding as parallel microscopic multi-pathway
+ diffusion-like processes. While the classical view
+ invoked pathways to solve the problem of searching for
+ the needle in the haystack, the pathway idea was then
+ seen as conflicting with Anfinsen's experiments showing
+ that folding is pathway-independent (Levinthal's
+ paradox). In contrast, the new view sees no inherent
+ paradox because it eliminates the pathway idea: folding
+ can funnel to a single stable state by multiple routes
+ in conformational space. The general energy landscape
+ picture provides a conceptual framework for
+ understanding both two-state and multi-state folding
+ kinetics. Better tests of these ideas will come when
+ new experiments become available for measuring not just
+ averages of structural observables, but also
+ correlations among their fluctuations. At that point we
+ hope to learn much more about the real shapes of
+ protein folding landscapes.",
+ ISSN = "1072-8368",
+ doi = "10.1038/nsb0197-10",
+ url = "http://www.nature.com/nsmb/journal/v4/n1/abs/nsb0197-10.html",
+ eprint = "http://www.nature.com/nsmb/journal/v4/n1/pdf/nsb0197-10.pdf",
+ note = "Pretty folding funnel figures.",
+}
projects / thesis.git / commitdiff
