Can We Accurately Describe the Structure of Adenine Tracts in B-DNA? Reference Quantum-Chemical Computations Reveal Overstabilization of Stacking by Molecular Mechanics

Investor logo
Investor logo
Investor logo

Warning

This publication doesn't include Faculty of Sports Studies. It includes Central European Institute of Technology. Official publication website can be found on muni.cz.
Authors

BANÁŠ Pavel MLÁDEK Arnošt OTYEPKA Michal ZGARBOVA Marie JURECKA Petr SVOZIL Daniel LANKAŠ Filip ŠPONER Jiří

Year of publication 2012
Type Article in Periodical
Magazine / Source Journal of Chemical Theory and Computation
MU Faculty or unit

Central European Institute of Technology

Citation
Web http://pubs.acs.org/doi/abs/10.1021/ct3001238?mi=tar3cx&af=R&pageSize=20&title=DNA
Doi http://dx.doi.org/10.1021/ct3001238
Field Biophysics
Keywords PLESSET PERTURBATION-THEORY; AMBER FORCE-FIELD; LIMIT INTERACTION ENERGIES; EMPIRICAL DISPERSION TERM; UNIQUE DINUCLEOTIDE STEPS; SEPARATE TOTAL ENERGIES; NUCLEIC-ACID STRUCTURES; BASIS-SET CONVERGENCE; BASE-PAIR STEPS; DYNAMICS SIMULATIONS
Attached files
Description Sequence-dependent local variations of helical parameters, structure, and flexibility are crucial for molecular recognition processes involving B-DNA. A-tracts, i.e., stretches of several consecutive adenines in one strand that are in phase with the DNA helical repeat, mediate significant DNA bending. During the past few decades, there have been intense efforts to understand the sequence dependence of helical parameters in DNA. Molecular dynamics (MD) simulations can provide valuable insights into the molecular mechanism behind the relationship between sequence and structure. However, although recent improvements in empirical force fields have helped to capture many sequence-dependent B-DNA properties, several problems remain, such as underestimation of the helical twist and suspected underestimation of the propeller twist in A-tracts. Here, we employ reference quantum mechanical (QM) calculations, explicit solvent MD, and bioinformatics to analyze the underestimation of propeller twisting of A-tracts in simulations. Although we did not identify a straightforward explanation, we discovered two imbalances in the empirical force fields. The first was overestimation of stacking interactions accompanied by underestimation of base-pairing energy, which we attribute to anisotropic polarizabilities that are not reflected by the isotropic force fields. This may lead to overstacking with potentially important consequences for MD simulations of nucleic acids. The second observed imbalance was steric clash between A(N1) and T(N3) nitrogens of AT base pairs in force-field descriptions, resulting in overestimation of the AT pair stretch in MD simulations. We also substantially extend the available set of benchmark estimated CCSD(T)/CBS data for B-DNA base stacking and provide a code that allows the generation of diverse base-stacking geometries suitable for QM computations with predefined intra- and interbase pair parameters.
Related projects:

You are running an old browser version. We recommend updating your browser to its latest version.

More info