Deglycosylation of alkylated nucleosides: a molecular orbital study

The glycoside bond in alkylated nucleosides is known to be more stable for $0^6$ -alkylguanosines and $0^4$ - alkylthymines, and less stable for $N^3$ - and $N^7$ -alkylpurine and $O^2$ - alkylpyrimidine nucleosides. These marked differences have been demonstrated through in vitro acidic hydrolysis and in vivo glycosylase repair. This study examines the relative facility of the deglycosylation reaction for various nucleosides through the use of theoretical indices derived from the semiempirical AM1 SCF-MO methodology, which furnish inferences much in consonance with experiment

Mutagenic significance of proton acidities in methylated guanine and thymine bases and deoxynucleosides: A theoretical study

Proton changes have been advanced as being the key molecular basis for the mutagenecity of alkylated DNA bases and nucleosides, leading to questions as to which protons are involved and whether the protic changes are tautomeric shifts or abstractions. This semiempirical molecular orbital study seeks to clarify the issue by examining the various possibilities open for these protic changes in a number of methylated guanines and thymines and their deoxynucleosides. Proton shifts leading to tautomer formation are not predicted as being thermodynamically favourable in most cases. The most feasible proton abstractions are predicted to involve the Watson-Crick protons in all cases, which corroborates Watson-Crick proton loss as providing the key molecular basis for the induction of point mutations. The calculated proton acidities correlate well with experimental data. The gas-phase deprotonation enthalpies for a number of alkylated nucleosides are found to correlate linearly with the solvent-phase pK(a) values. The theoretically calculated enthalpies in a simulated aqueous solvent phase of the deprotonation reactions of various nucleic acid bases are also found to have good linear correlations with experimental pK(a) values. The consensus of these calculations is that O-6-alkyldeoxyguanosines, and O-2- and O-4-alkyldeoxythymidines would be mutagenic while N-7-alkyldeoxyguanosines would not be mutagenic (as experiment indicates). The untested N-3-methyldeoxyguanosine is predicted to be mutagenic. (C) 1997 Elsevier Science B.V

A semi-empirical SCF-MO study on the base-pairing properties of 8-oxopurines: significance for mutagenicity

C8-Oxidised purines like 7-hydro-8-oxoguanine (8OG) and 7-hydro-8-oxoadenine (8OA) are known as products of oxidative DNA damage. Semiempirical molecular orbital calculations at the PM3 SCF-MO level are used to investigate the base-pairing properties of these bases in an attempt to understand their mutagenic properties. A detailed analysis of the base-pairing properties of these bases leads to an identification of the most probable pairing schemes involved in mutagenic base-mispairing. It is suggested that both bases are capable of inducing transversional as well as transitional mutations via base-mispairing. The results presented are largely in consonance with available experimental reports

Structure and dynamics of zymogen human blood coagulation factor X.

The solution structure and dynamics of the human coagulation factor X (FX) have been investigated to understand the key structural elements in the zymogenic form that participates in the activation process. The model was constructed based on the 2.3-A-resolution x-ray crystallographic structure of active-site inhibited human FXa (PDB:1XKA). The missing gamma-carboxyglutamic acid (GLA) and part of epidermal growth factor 1 (EGF1) domains of the light chain were modeled based on the template of GLA-EGF1 domains of the tissue factor (TF)-bound FVIIa structure (PDB:1DAN). The activation peptide and other missing segments of FX were introduced using homology modeling. The full calcium-bound model of FX was subjected to 6.2 ns of molecular dynamics simulation in aqueous medium using the AMBER6.0 package. We observed significant reorientation of the serine-protease (SP) domain upon activation leading to a compact multi-domain structure. The solution structure of zymogen appears to be in a well-extended conformation with the distance between the calcium ions in the GLA domain and the catalytic residues estimated to be approximately 95 A in contrast to approximately 83 A in the activated form. The latter is in close agreement with fluorescence studies on FXa. The S1-specificity residues near the catalytic triad show significant differences between the zymogen and activated structures