Theoretical and computational modeling of rna-ligand interactions
Authors:   , Zhou Yuanzhe 
Published: May 2022

Ribonucleic acid (RNA) is a polymeric nucleic acid that plays a variety of critical roles in gene expression and regulation at the level of transcription and translation. Recently, there has been an enormous interest in the development of therapeutic strategies that target RNA molecules. Instead of modifying the product of gene expression, i.e., proteins, RNAtargeted therapeutics aims to modulate the relevant key RNA elements in the disease-related cellular pathways. Such approaches have two significant advantages. First, diseases with related proteins that are difficult or unable to be drugged become druggable by targeting the corresponding messenger RNAs (mRNAs) that encode the amino acid sequences. Second, besides coding mRNAs, the vast majority of the human genome sequences are transcribed to noncoding RNAs (ncRNAs), which serve as enzymatic, structural, and regulatory elements in cellular pathways of most human diseases. Targeting noncoding RNAs would open up remarkable new opportunities for disease treatment. The first step in modeling the RNA-drug interaction is to understand the 3D structure of the given RNA target. With current theoretical models, accurate prediction of 3D structures for large RNAs from sequence remains computationally infeasible. One of the major challenges comes from the flexibility in the RNA molecule, especially in loop/junction regions, and the resulting rugged energy landscape. However, structure probing techniques, such as the ���selective 20-hydroxyl acylation analyzed by primer extension��� (SHAPE) experiment, enable the quantitative detection of the relative flexibility and hence structure information of RNA structural elements. Therefore, one may incorporate the SHAPE data into RNA 3D structure prediction. In the first project, we investigate the feasibility of using a machine-learning-based approach to predict the SHAPE reactivity from the 3D RNA structure and compare the machine-learning result to that of a physics-based model. In the second project, in order to er-friendly tool for RNA biologists, we developed a fully automated web interface, ���SHAPE predictoR��� (SHAPER) for predicting SHAPE profile from any given 3D RNA structure. In a cellular environment, various factors, such as metal ions and small molecules, interact with an RNA molecule to modulate RNA cellular activity. RNA is a highly charged polymer with each backbone phosphate group carrying one unit of negative (electronic) charge. In order to fold into a compact functional tertiary structure, it requires metal ions to reduce Coulombic repulsive electrostatic forces by neutralizing the backbone charges. In particular, Mg2+ ion is essential for the folding and stability of RNA tertiary structures. In the third project, we introduce a machine-learning-based model, the ���Magnesium convolutional neural network��� (MgNet) model, to predict Mg2+ binding site for a given 3D RNA structure, and show the use of the model in investigating the important coordinating RNA atoms and identifyitifs. Besides Mg2+ ions, small molecules, such as drug molecules, can also bind to an RNA to modulate its activities. Motivated by the tremendous potential of RNA-targeted drug discovery, in the fourth project, we develop a novel approach to predicting RNA-small molecule binding. Specifically, we develop a statistical potential-based scoring/ranking method (SPRank) to identify the native binding mode of the small molecule from a pool of decoys and estimate the binding affinity for the given RNA-small molecule complex. The results tested on a widely used data set suggest that SPRank can achieve (moderately) better performance than the current state-of-art models.