Projects / Programmes
Molecular dynamics simulations of nucleic acids: structure, dynamics and thermodynamic stability
| Code |
Science |
Field |
Subfield |
| 1.04.01 |
Natural sciences and mathematics |
Chemistry |
Phyisical chemistry |
| Code |
Science |
Field |
| P400 |
Natural sciences and mathematics |
Physical chemistry |
molecular dynamics, nucleic acids, DNA minor groove, free energy, RNA hairpins, computer simulations, statistical mechanics, thermodynamics, drug-DNA interactions, drug design
Researchers (1)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
22603 |
PhD Jožica Dolenc |
Chemistry |
Head |
2007 - 2008 |
52 |
Organisations (1)
Abstract
Objective of this proposal is to obtain a further insight into the structure, dynamics and thermodynamics of DNA, RNA and drug-DNA interactions through atomistic modeling of nucleic acids using molecular dynamics (MD) computer simulations. Molecular dynamics simulations are one of the most rigorous technique for modeling macromolecular systems. They produce a complete, quantitative microscopic description of the structure and dynamics of macromolecules in solution. The research effort will be focused along the following three directions: i) using molecular dynamics simulations in explicit solvent the importance of hydrogen bonding and van der Waals contacts to the stability of complexes formed between small ligands and DNA minor groove will be investigated. Small molecules that bind to the minor groove of DNA are known to interfere with gene expression at the level of transcription and replication and are of considerable interest to the discovery of novel drugs; ii) the technique of single step perturbation will be employed to calculate relative free energies of binding of netropsin to a series of different base pair sequences in the DNA minor groove. It has been shown several times that the thermodynamics of binding of netropsin to the DNA minor groove depends strongly on the sequence of the base pairs in the binding site. The technique of single step perturbation is a very efficient technique in which free energy differences among a series of similar compounds can be calculated from a single simulation of a common reference state; iii) with the goal to understand the effect of the closing base-pair on the stability of the RNA hairpins the structural, dynamical and thermodynamical properties of RNA tetraloops will be analysed and compared using molecular dynamics simulations and free energy calculations. Hairpins are the most abundant element of RNA secondary structure and they play an important part in many cellular processes.
Significance for science
With extensive molecular dynamics simulations of netropsin-DNA complexes I have calculated the binding affinities of netropsin to different binding sites in the DNA minor groove using single-step perturbation and thermodynamic integration techniques. Since the experimental data on netropsin-DNA binding affinities is limited to a small number of different DNA binding sequences the results of the calculations present an important contribution to understanding of netropsin-DNA interactions. The calculated Gibbs free energies confirm experimental observations that a guanin-cytozin (GC) base pair in the middle of the binding site hinders the binding of netropsin to DNA. Morover, the results also show that a GC base pair at the end of the binding site either has no influence on the binding affinity or it enhances it. With the aim of understanding the physical laws governing the drug-DNA binding affinity dependence on the DNA minor groove base pair sequence, I performed detailed structural and thermodynamic analyses of the simulated complexes. The results have shown that the standard energetic analysis of drug-DNA interactions, such as hydrogen bonding or van der Waals interactions, is not enough to explain the drug-DNA binding affinities. The entropic contributions to the Gibbs free energy of binding must be taken into the account. This observation has been often made in the literature; however, due to the difficulties in quantifying the entropic contributions both experimentally and by computer simulation, these are only rarely reported. In this research project I calculated the energetic and entropic contributions to the Gibbs free energy of binding using the well-validated and computationally intensive thermodynamic integration method. The results have shown that the entropic contribution to the Gibbs free energy of binding of netropsin to the DNA minor groove greatly depends on the sequence of base pairs in the DNA minor groove; in certain cases it is even as large as the energetic contribution. Quantitative determination of the changes in entropy in the drug-DNA complex formation is very important for the pharmaceutical industry since it confirms that not only the energetics but also the flexibility of both the ligand and receptor should be taken into account in the design of new drugs.
The comparison of the relative Gibbs free energies calculated with the fast single-step perturbation method, which has been developed for screening in the pharmaceutical industry, to the relative Gibbs free energies calculated with the well-validated but much more computationally demanding thermodynamic integration method allowed me to assess the accuracy of the single-step perturbation method. The results show that the single-step perturbation method gives good estimates of ligand-DNA binding affinities when the ligands or the receptors being investigated are chemically similar enough. If not, then the results of the single-step perturbation method may be unpredictable since it is difficult to describe dissimilar systems with a single reference state.
Significance for the country
Computer simulations are an important tool in various fields where theory and experiment meet. At the Faculty of Chemistry and Chemical Technology of the University of Ljubljana (FKKT, UL) it is not yet very common to complement experiment with computer simulation. The postdoctoral project in which I have collaborated with one of the leading groups for biomolecular simulations, headed by Prof. W. F. van Gunsteren at the Swiss Federal Institue of Technology Zurich (ETHZ), enabled the transfer of new knowledge and pedagogical experience to Slovenia as well as promoting our scientific work abroad. In addition, the postdoctoral project resulted in important scientific insights, which augment the experimental research of the Chair of Physical Chemistry, FKKT, UL, since thez give an explanation of the thermodynamic experimental results at the atomistic level.
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