Commit d1a4b85a by Carlos GO

### done

parent cb06c6dc

224 KB

224 KB

171 KB

 ... ... @@ -93,10 +93,14 @@ \begin{frame} \frametitle{RNA} \begin{itemize} \item RNA can fulfill virtually all needs of life (information carrying, catalytic activity). All organisms have RNA. \item Folds hierarchically from a sequence to a 2D scaffold, to a full 3D structure. \end{itemize} \begin{figure}[h!] \centering \includegraphics[width=0.6\textwidth]{struc.jpeg} \caption{This is RNA. ~\cite{reinharz2016algorithmic}} \includegraphics[width=0.5\textwidth]{struc.jpeg}~\cite{reinharz2016algorithmic} \label{fig:rna} \end{figure} ... ... @@ -138,7 +142,7 @@ \frametitle{{\bf Project I:} \maternal, How do complex structures evolve?} \begin{itemize} \item \problemtag How can energetically unfavorable structures appear? \item \problemtag How can populations reach energetically unfavorable structures? \item \ideatag Model the distribution of mutants. \end{itemize} ... ... @@ -159,6 +163,13 @@ \begin{frame} \frametitle{Sampling methods.} \begin{itemize} \item Model probability of $k$ mutant sequence-structure $(\omega, s)\in \mathbb{S}_{\omega_0}^k$ with Boltzmann distribution: \mathbb{P}(\omega, s) = \frac{e^{\frac{-E(\omega, s)}{RT}}}{\mathcal Z},\qquad \mathcal Z = \sum_{(\omega', s')\in \mathbb{S}_{\omega_0}^k}e^{\frac{-E(\omega', s')}{RT}}. \end{itemize} \begin{figure} \includegraphics[width=\textwidth]{maternal.pdf} \end{figure} ... ... @@ -180,7 +191,7 @@ \begin{itemize} \item Thermodynamic ensembles could have shaped the discovery of complex structures. \item More complex evolutionary explorations needed to explain full distribution. \item Manuscript accepted at RNA journal. \cite{oliver2019necessary} \item Manuscript accepted at RNA journal. \cite{oliver2017necessary} \end{itemize} \item Next Steps \begin{itemize} ... ... @@ -233,7 +244,7 @@ \item The majority of RNA ligands are discovered through phenotypic screens and later attributed to RNA binding. (e.g. ribocil) \item Computational approaches focus on direct docking. \begin{itemize} \item DOCK 6.0 (2015) \item DOCK 6.0 (2015) \cite{lang2009dock} \item Molecular Forecaster (2006) (Moitessier, \textcolor{red}{Collaborators}) \item LigandRNA (Bujnicki) \end{itemize} ... ... @@ -269,6 +280,10 @@ \begin{frame} \frametitle{Results} \begin{itemize} \item For each input pocket, how much does \rnamigos increase the probability of finding the true ligand? \end{itemize} \begin{figure}[htb!] \begin{subfigure}{0.45\textwidth} \includegraphics[width=\textwidth]{violins.pdf} ... ... @@ -289,6 +304,10 @@ \begin{frame} \frametitle{Results} \begin{itemize} \item Using the 3D structure graph we can increase the probability of retrieving the true ligand. \end{itemize} \begin{figure} \centering \includegraphics[width=\textwidth]{tree_ligs.pdf} ... ... @@ -305,11 +324,12 @@ \item Conclusions \begin{itemize} \item Binding pocket graphs contain signal that can be exploited for RNA drug discovery. \item Preparing for resubmission (Preprint ~\cite{oliver2019extended}) \end{itemize} \item Next Steps \begin{itemize} \item \begin{quote} ... holds promise, and the method introduced did seem innovative. Without more detailed retrospective studies for ligand enrichment,..., and without prospective prediction and testing for new, non-trivial ligands, the manuscript will not command the attention of the broad audience that PNAS attracts. In its current form, the manuscript may be better suited to a more specialized journal, such as JCIM. \end{quote} \item Validate signal with {\bf computational docking}. \item Validate signal with {\bf computational docking} ~\cite{lang2009dock}. \end{itemize} \end{itemize} ... ... @@ -343,19 +363,19 @@ \frametitle{Related work} \begin{itemize} \item We want a motif finding tool that works on graphs and is inductive. \item We want a fuzzy motif finding tool that works on graphs. \end{itemize} \begin{table}[] \resizebox{\textwidth}{!}{% \begin{tabular}{lllll} \hline & flexible motifs & all ss & graph-based & inductive \\ \hline rna3dmotif & \xmark & \xmark & \cmark & \xmark \\ \hline 3d motif atlas & $\sim$ & \xmark & $\sim$ & \xmark \\ \hline carnaval & \xmark & \xmark & \cmark & \xmark \\ \hline RNAMSC \cite{ge2018novo} & \cmark & \xmark & \xmark & \xmark \\ \hline {\bf \vernal} & \cmark & \cmark & \cmark & \cmark & flexible motifs & all ss & graph-based \\ \hline rna3dmotif ~\cite{djelloul2009algorithmes} & \xmark & \xmark & \cmark \\ \hline RNA 3D Motif Atlas ~\cite{petrov2013automated} & $\sim$ & \xmark & $\sim$ \\ \hline CaRNAval ~\cite{reinharz2018mining} & \xmark & \xmark & \cmark \\ \hline RNAMSC \cite{ge2018novo} & \cmark & \xmark & \xmark \\ \hline {\bf \vernal} & \cmark & \cmark & \cmark \end{tabular}% } \end{table} ... ... @@ -376,9 +396,10 @@ \end{figure} \end{frame} \begin{frame}{Picking $d$: Edge histogram distance} Idea: similar rings will have similar distributions of edge types. \begin{frame}{Node similarity function} \begin{itemize} \item \ideatag Similar rings will have similar distributions of edge types. \end{itemize} k_L(u,v) := \sum_{l=0}^{L-1} \lambda^{l} d(R_u^l, R_v^l) ... ... @@ -392,7 +413,7 @@ \begin{figure} \centering \includegraphics[width=0.4\textwidth]{k.pdf} \includegraphics[width=0.3\textwidth]{k.pdf} \end{figure} \end{frame} ... ... @@ -437,7 +458,7 @@ \begin{frame} \frametitle{Full} \frametitle{Full Framework} \begin{figure} ... ... @@ -471,6 +492,7 @@ \frametitle{First Look At Motif Learning} \begin{itemize} \item \problemtag Always assigning the same motif \item Might need extra reconstruction term, or loss function weights need adjusting. \end{itemize} \begin{figure} ... ... @@ -495,8 +517,8 @@ \item Once we've identified related structures we need to align them to build: \begin{itemize} \item Analysis of conserved (functional) interactions. \item Statistical models from consensus (\texttt{BayesPairing}) \item Predictive models from distances (\rnamigos) \item Statistical models from consensus (\texttt{BayesPairing} ~\cite{sarrazin2019automated}) \item Predictive models from distances (\rnamigos ~\cite{oliver2019extended}) \end{itemize} \item Graph alignment $\sim$ sequential graph editing or node matching. \end{itemize} ... ... @@ -521,6 +543,7 @@ \begin{itemize} \item Existing methods focus on strict edge conservation. \item Mostly applied to aligning protein-protein interaction networks. \item Major tools rely on {\it a priori} node and edge conservation heuristics \end{itemize} ... ... @@ -528,12 +551,12 @@ \resizebox{\textwidth}{!}{% \begin{tabular}{lllll} \hline & Node cost & Edge Cost & Custom Cost & Inductive \\ \hline IsoRank & \cmark & $\sim$ & \cmark & \xmark \\ \hline GRALL & \cmark & \xmark & $\sim$ & \xmark \\ \hline WAVE & \xmark & $\sim$ & \xmark & \xmark \\ \hline Gromov-Wasserstein \cite{ge2018novo} & \cmark & \xmark & \xmark & \xmark \\ \hline {\bf \garl} & \cmark & \cmark & \cmark & \cmark & Custom Node Cost & Edge Info & Node Order \\ \hline IsoRank ~\cite{singh2007pairwise} & \xmark & \xmark & \xmark & \\ \hline GRALL ~\cite{malod2015graal} & \cmark & \xmark & \xmark & \\ \hline WAVE ~\cite{sun2015simultaneous} & \cmark & $\sim$ & \xmark & \\ \hline Gromov-Wasserstein ~\cite{xu2019gromov} & \xmark & \xmark & \xmark & \\ \hline {\bf \garl} & \cmark & \cmark & \cmark \end{tabular}% } \end{table} ... ... @@ -543,18 +566,40 @@ \begin{frame} \frametitle{RL-based graph alignment} \begin{itemize} \item Actions: pair of nodes to align \item State: Graph embedding (GCNs) \item Reward: user-defined cost function. \item \problemtag Accomodating arbitrary cost functions without specialized heuristics \item \ideatag Abstract the cost as an environment factor in RL. \begin{itemize} \item {\bf Actions}: pair of nodes to align \item {\bf State/Value:} Graph embedding (GCNs) \item {\bf Reward}: user-defined cost function. \end{itemize} \end{itemize} \begin{figure} \includegraphics[width=0.6\textwidth]{garl.pdf} \includegraphics[width=0.5\textwidth]{garl.pdf} \end{figure} \end{frame} \begin{frame} \frametitle{Current Status \& Next Steps} Current Status \begin{itemize} \item Implementation functional \end{itemize} Next Steps \begin{itemize} \item Initial validation \end{itemize} \begin{figure} \centering \includegraphics[width=0.65\textwidth]{action_value.pdf} \end{figure} \end{frame} \section{Conclusion} ... ... @@ -670,6 +715,22 @@ \bibliography{biblio} \end{frame} \begin{frame} \frametitle{We can use \rnamigos to find binding sites} \includegraphics[width=0.3\textwidth]{3d0x_find.png} \includegraphics[width=0.3\textwidth]{3ox0_find.png} \includegraphics[width=0.3\textwidth]{3suy_find.png} \end{frame} \begin{frame} \frametitle{Distribution of RNA ligands} \begin{figure} \includegraphics[width=0.9\textwidth]{all_ligs_tsne_wide_labels.pdf} \end{figure} \end{frame} \begin{frame}{Picking $d$: Graphlet Distance} Idea: Compare structure of nodes in each ring with alignments. ... ...