Investigation of the Roles of Aromatic Cages in Molecular Recognition of Ligands in Proteins
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University of Toledo / OhioLINK
2019
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=toledo1576248457002834 |
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English |
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Chemistry |
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Chemistry Chejerla, Giridhar Raju Investigation of the Roles of Aromatic Cages in Molecular Recognition of Ligands in Proteins |
| author |
Chejerla, Giridhar Raju |
| author_facet |
Chejerla, Giridhar Raju |
| author_sort |
Chejerla, Giridhar Raju |
| title |
Investigation of the Roles of Aromatic Cages in Molecular Recognition of Ligands in Proteins |
| title_short |
Investigation of the Roles of Aromatic Cages in Molecular Recognition of Ligands in Proteins |
| title_full |
Investigation of the Roles of Aromatic Cages in Molecular Recognition of Ligands in Proteins |
| title_fullStr |
Investigation of the Roles of Aromatic Cages in Molecular Recognition of Ligands in Proteins |
| title_full_unstemmed |
Investigation of the Roles of Aromatic Cages in Molecular Recognition of Ligands in Proteins |
| title_sort |
investigation of the roles of aromatic cages in molecular recognition of ligands in proteins |
| publisher |
University of Toledo / OhioLINK |
| publishDate |
2019 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1576248457002834 |
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AT chejerlagiridharraju investigationoftherolesofaromaticcagesinmolecularrecognitionofligandsinproteins |
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1719456765235429376 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-toledo15762484570028342021-08-03T07:13:36Z Investigation of the Roles of Aromatic Cages in Molecular Recognition of Ligands in Proteins Chejerla, Giridhar Raju Chemistry Molecular recognition of a ligand in its binding protein plays an essential role in all kinds of biological processes including signal transduction, immune recognition and enzyme catalysis. It is now widely accepted that the driving forces underlying molecular recognition are the nonbonded interactions (i.e., hydrogen bonding, cation–π interactions, π–π stacking interactions, and CH-π interactions) between the ligand and its interacting residues of the targeted protein. The primary objective of this research is to investigate the roles of aromatic cages in molecular recognition of ligands in proteins. Aromatic cage is a natural occurrence in proteins, consisting of multiple aromatic residues situated in geometric proximity with a central cavity. Due to its aromatic nature and geometry, aromatic cages can participate in molecular recognition of cations, aromatic groups and aliphatic chains through cation-π interactions, π-π stacking interactions and CH-π interactions, respectively. First, we start with mining the aromatic cages via a combination of literature search and data mining of PDB databank, which resulted in the establishment of an in-house databank of aromatic cages. Then, the aromatic cages are classified into three groups according to the nature of the interacting ligands and divided into cation-π interactions group, π-π stacking interactions group and CH-π interactions group. For each of the three groups, the binding modes of interaction are examined and thoroughly analyzed, and the strengths of intermolecular interactions are quantified by means of advanced quantum chemical calculations at the B2PLYPD3/cc-pvDZ level of theory. The data mining analysis resulted in (a) three high resolution (2.5 Å or better) X-ray crystal structures of proteins in which the aromatic cage interacting with the bound ligands via CH-π interactions (Leucine bound to leucine-specific binding; 2-cyclohexylaminobenzoicacid bound to phenazine biosynthesis protein A/B; Norleucine bound to Histone-lysine N-methyltransferase EHMT2); and (b) four high resolution X-ray crystal structures of proteins with the intrinsic aromatic cage interacting with the bound ligands via π-π stacking interactions (phenylalanine bound to the hypothetical protein yqjY; Phenylalanine bound to putative 4-amino-4-deoxychorismate lyase; Benzamidine bound to histone-arginine methyltransferase; and Tyrosine bound to Lysine-specific demethylase 4A). In both cases, the intermolecular interaction energies calculated at the B2PLYPD3/cc-pvDZ level of theory are negative, indicating that aromatic cages act as an “attractive” binders for both aliphatic and aromatic moieties of ligands. This is in accord with the biological functions of the proteins as the native ligand-binding proteins or as the targets of inhibitors.The role of aromatic cages in molecular recognition of ligand in proteins via cation-π interactions is exemplified by the binding of methylated histone tails with the “reader proteins”. As a matter of fact, one focused area of research in this thesis is molecular recognition involving histone lysine methylation. Lysine methylation is one of the most important post-translation modifications in histone remodeling since it alters directly the structure of the chromatin thereby act as binding target for the nuclear proteins. The aromatic cages formed of Phe, Trp, Tyr residues of proteins that belong to the Royal superfamily and the PHD finger superfamily (known as the “reader proteins”) exhibit the tendency to interact with the methylated lysine of the histones through cation-π interactions. Interestingly, the lysine residues are known to undergo methylation in three different states: mono-methyl lysine (Kme1), di-methyl lysine (Kme2) and tri-methyl lysine (Kme3). The methyllysine readers play an important role in selecting the methylation site on the targeted lysine on histones through a conserved mechanism in which the side chain of the methylated lysine is inserted into the aromatic cage of the reader domain belonging to “Chromatin remodeling proteins”. One of the important questions needed to be answered was, how does the aromatic cage of the reader protein recognize the targeted lysine site? Additionally, how does the degree of the methylation state of the lysine influences the molecular recognition of the methylated histone tail by the aromatic cages of the reader proteins? To address those important questions, we performed a large-scale data mining of the PDB databank, which resulted in a total of 150 complexes consist of aromatic cages interacting with methylated lysine residues. Among them are 81 Kme3, 38 Kme2 and 31 Kme1. This large number of complexes provided an opportunity for a systematic analysis of energetics for intermolecular (binding) interactions between aromatic cages of readers and methylated lysines at varying methylated states. The strengths of intermolecular interaction energies are quantified by means of Density Functional Theory (DFT) at the B2PLYPD3/cc-pvDZ level. It was found that the average intermolecular interaction energy increases as the extent of lysine methylation increases, ranging from -4.5 kcal/mol, through -11.0 kcal/mol, to -14.5 kcal/mol for Kme1, Kme2 and Kme3, respectively. It is worth noting that the average intermolecular interaction energy for the unmethylated lysine is estimated to be -2.4 kcal/mol at the same level of theory. It is our belief that this substantial difference in intermolecular interaction energies of incrementally methylated lysines may be a strong indication that energetics is an important controlling factor in mutual molecular recognition of incrementally methylated lysines with the aromatic cages of the reader proteins belonging to “Chromatin remodeling proteins”. This agrees with the experimentally observed stage-specific biological responses to lysine methylation. 2019 English text University of Toledo / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=toledo1576248457002834 http://rave.ohiolink.edu/etdc/view?acc_num=toledo1576248457002834 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |