From: W. Trevor King Date: Mon, 22 Feb 2010 21:36:25 +0000 (-0500) Subject: Added pathway / landscape folding model paragraph X-Git-Tag: v1.0~452 X-Git-Url: http://git.tremily.us/?a=commitdiff_plain;h=96237f4dfe4fe90895e36f36199235cfb8282560;p=thesis.git Added pathway / landscape folding model paragraph --- diff --git a/tex/src/figures/schematic/dill97-fig4.png b/tex/src/figures/schematic/dill97-fig4.png new file mode 100644 index 0000000..8a37e9a Binary files /dev/null and b/tex/src/figures/schematic/dill97-fig4.png differ diff --git a/tex/src/introduction/main.tex b/tex/src/introduction/main.tex index b552dc4..03164c8 100644 --- a/tex/src/introduction/main.tex +++ b/tex/src/introduction/main.tex @@ -13,28 +13,28 @@ conformations and behaviors. Bulk measurements average over these 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} @@ -52,22 +52,39 @@ remarkably difficult problems. \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 diff --git a/tex/src/root.bib b/tex/src/root.bib index c4f5501..eafe4c8 100644 --- a/tex/src/root.bib +++ b/tex/src/root.bib @@ -67,6 +67,8 @@ @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."} @@ -2923,17 +2925,17 @@ note = {A nice introduction to some quantitative ramifications of the funnel ene } -@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", @@ -7470,3 +7472,46 @@ doi = "DOI: 10.1016/0006-291X(90)90526-S", 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.", +}