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Exceptional Thermodynamic Stability of DNA Duplexes Modified by Nonpolar Base Analogues Is due to Increased Stacking Interactions and Favorable Solvation: Correlated Ab Initio Calculations and Molecular Dynamics Simulations
Author(s) -
Řeha David,
Hocek Michal,
Hobza Pavel
Publication year - 2006
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200501126
Subject(s) - stacking , solvation , random hexamer , molecular dynamics , chemistry , base pair , thymine , crystallography , base (topology) , binding energy , solvation shell , ab initio , interaction energy , pair potential , computational chemistry , thermodynamics , dna , molecule , atomic physics , physics , organic chemistry , mathematical analysis , mathematics , biochemistry
Abstract The geometries of DNA hexamer (5′‐GGAACC‐3′) and DNA 13‐mer (5′‐GCGTACACATGCG‐3′) have been determined by molecular dynamics (MD) simulations using an empirical force field. The central canonical base pair was replaced by a pair of nonpolar base analogues, 2,2′‐bipyridyl and 3‐methylisocarbostyril. The stabilization energy of the model system (model A) consisting of a central base pair (base‐analogue pair) and two neighboring base pairs was determined by the RI‐MP2 method using an extended aug‐cc‐pVDZ basis set. The geometry of the model was averaged from structures determined by MD simulations. The role of the solvent was covered by the COSMO continuum solvent model and calculations were performed for a larger model system (model B) which also contained a sugar–phosphate backbone. The total stabilization energies of the unperturbed system and the system perturbed by a base‐analogue pair (model A) were comparable to the stability of both duplexes experimentally determined. This is due to large stacking interaction energy of the base‐analogue self‐pair which compensates for the missing hydrogen‐bonding energy of the replaced adenine⋅⋅⋅thymine base pair. The selectivity of the base‐analogue pair was reproduced (model B) when their desolvation energy was included with the interaction energy of both strands determined by the approximate SCC‐DFTB‐D method.