Date of Award
4-1-2024
Language
English
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
College/School/Department
Department of Chemistry
Dissertation/Thesis Chair
Alan A.A.C Chen
Committee Members
Jia Sheng, Alexander Shekhtman, Gabriele Fuchs
Keywords
conformational-selection, METADYNAMICS, Molecular Dynamics (MD), molecular recognition mechanism, RNA binding pocket, small molecule ligand
Subject Categories
Computational Chemistry
Abstract
From my PhD research, under Amber99-Chen-Garcia force field, umbrella sampling and MD simulation helped us found that the 2’-5’ phosphodiester RNA backbone linkage modification on in vitro selected neomycin RNA aptamer can transfer it to ‘amikacin RNA aptamer’ by changing the conformation and backbone rigidity of the RNA binding pocket, which further influenced the binding mode and binding pathway of amikacin. Furthermore, under the same force field, metadynamics was found more powerful for simulating the binding pathway, binding mechanism and predicting binding modes of small molecule ligand recognizing its RNA target by filling up all energy basins on free energy surface of the binding pathway with extra Gaussian potential, which was well-trained on five small molecule/RNA binding pocket systems. This metadynamics prediction method training study also discovered a theory of ‘conformational-selection model of small molecule binding with different degree of induced-fit effect on RNA target based on the rigidity of small molecule ligand’ for the binding model of small molecule ligand/RNA binding pocket recognition system. Furthermore, this well-trained metadynamics simulation prediction method was firstly applied to help us found that 2’-5’ linkage modifications on FMN RNA aptamer narrowed the width of the frontside opening of RNA binding pocket, at the same time, the backside opening became wider, which changed the binding pathway and binding mode of FMN to ‘upside down’. Secondly, this well-trained metadynamics simulation prediction method helped us refining the NMR binding mode of small molecule splicing modifier SMN-C5/RNA duplex and further predicted a new mechanism of splicing modifier SMN-C5 promoting SMN2 exon 7 inclusion for treating spinal muscular atrophy (SMA). In sum, Amber99-Chen-Garcia force field showed its power and potential of capturing RNA-small molecule ligand interactions correctly. Umbrella sampling showed its power and potential of simulating unbinding events and calculating ΔG bind/unbind for RNA-small molecule ligand complex correctly. With a good force field of Amber99-Chen-Garcia and good CVs selection, metadynamics showed its power and potential of predicting binding modes, binding pathway and binding mechanism of RNA-small molecule ligand recognition correctly.
Recommended Citation
Bai, Zhixue, "Decoding Molecular Recognition Mechanism Of Small Molecule Ligand-Rna Binding Pocket Systems Using Molecular Dynamics And Metadynamics" (2024). Legacy Theses & Dissertations (2009 - 2024). 3287.
https://scholarsarchive.library.albany.edu/legacy-etd/3287