Physical Nature of Interactions within the Active Site of Cytosine-5-methyltransferase

Abstract

The physical nature of interactions within the active site of cytosine-5-methyltransferase (CMT) was studied using a variation-perturbation energy decomposition scheme defining a sequence of approximate intermolecular interaction energy models. These models have been used to analyze the catalytic activity of residues constituting cytosine-5-methyltransferase active site as well their role in the binding group of de novo designed inhibitors. Our results indicate that Glu119, Arg163, and Arg165 appear to play the dominant role in stabilizing the protonated transition state structure and their influence can be qualitatively approximated by electrostatic interactions alone. The stabilization of neutral structures of the alternative reaction pathway is small, which might suggest the protonated pathway as preferred by the enzyme. Exchange and delocalization terms are negligible in most cases, or they cancel each other to some extent. Interactions of inhibitors with the CMT active site are dominated by electrostatic multipole contributions in analogy with previously studied transition state analogue inhibitors of leucyl aminopeptidase.

Quantum chemical analysis of reaction paths in chorismate mutase: Conformational effects and electrostatic stabilization

“…Similar results, i.e. interactions dominated by electrostatics and mutual cancellation of correlation, delocalization, and exchange components has been found in other enzymes, for example cytosine-5-methyltransferase [20] and leucine aminopeptidase [21]. The aim of this work is to investigate the interactions along the whole path, in order to analyse the stabilization of the reacting system provided by residues at every stage of the reaction.…”

Mutual Relationship between Stacking and Hydrogen Bonding in DNA. Theoretical Study of Guanine−Cytosine, Guanine−5-methylcytosine, and Their Dimers

“…The different behavior when a thymine base is replaced by a uracil one, can now be studied by methylation of the cytosine base to obtain the 5-methlcytosine (C′). DNA methylation in higher eukaryotes occurs at cytosines in CpG dinucleotides by the transfer of a methyl group from S-adenosylmethionine to the C5 position of cytosine catalyzed by DNA methyltransferases. − Methylation adds extra information to the DNA that is not encoded in the sequence. This so-called epigenetic information has many important biological functions.…”

“…DNA methylation in higher eukaryotes occurs at cytosines in CpG dinucleotides by the transfer of a methyl group from S-adenosylmethionine to the C5 position of cytosine catalyzed by DNA methyltransferases. [17][18][19][20] Methylation adds extra information to the DNA that is not encoded in the sequence. This so-called epigenetic information has many important biological functions.…”

Effect of Noncovalent Interactions on the n-Butylbenzene···Ar Cluster Studied by Mass Analyzed Threshold Ionization Spectroscopy and ab initio Computations

“…However, many molecular phenomena are determined by much weaker intermolecular forces that originate from noncovalent interactions and are of quite different nature. Bulk properties of gases, liquids, solutions and solids, as well as most biological processes are determined by noncovalent interactions. – Large van der Waals (vdW) complexes, consisting of an organic aromatic molecule bound to rare-gas atoms, are expected to provide basic information on the structural, energetic, and dynamic manifestations of intermolecular interactions in these well-characterized, large chemical systems. , With the increasing improvements in spectroscopic techniques, detailed studies of structure, energetics, and electronic-vibrational level structure along with the intra- and inter molecular dynamics can now be explored using clusters produced in molecular beams. – …”