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Towards simulating fully charged protein-DNA systems in water: Zif268-DNA as a test case
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Physical Chemistry.
1999 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis, we develop a computing strategy to simulate fully charged protein-DNA systems with a general force field (GROMOS87). The ions neutralizing the phosphates (P-ions) are submitted to global symmetry constraints. A model exhibiting ionic-atmosphere effects on mobile P-ions was implemented via very weak restraint forces. The same set of molecular parameters for atom types is used for both the protein and the DNA oligomer. Protein-protein, DNA-DNA, protein-DNA and water-water interactions are the invariant part of the simulation framework. The corrections found necessary to describe solvent-solute interactions are incorporated now as standard.

The computing framework was tested with Zif268-DNA complex. Zif268 is a 3-zinc finger domain found in the growth factor-inducible protein zif268 related to the transcription factor gene zif268. The analyses show that the rigged GROMOS87 force field yields a fairly appropriate representation of the fully charged protein-DNA complex in solution.

The DNA sequence used 5'-GCGTGGGGCGT-3' represents one possible high-affinity binding site. A second one where thymine (T4) was mutated into a guanine (G4) was tested. The results show protein-DNA recognition sites to behave in a similar manner thereby opening an opportunity to study possible dynamic recognition determinants. One aspect of it was addressed by studying the zinc-fingers alone. In water, the protein shows a trend to adopt an extend finger conformation. To disentangle solvation effects from intrinsic properties, a set of dry MD trajectories were calculated. Result: the accessible configurational space also includes elongated conformations resembling those found from another zinc-finger protein (transcription factor IIIA) experimentally determined in solution; in the complex, Zif hugs the DNA. After soaking the in vacuo configurations, the MD results suggest Zif268 in solution may have an elongated average conformation of the 3-finger polypeptide.

This put the functionality - defined as the ability to make the proper protein-DNA complex- on the protein's ability to sustain large conformational changes relating it to its linkers dynamic properties. All the information gathered so far can be used to construct a set of two-finger chimeras as templates in modeling the two zinc-finger negative regulator mediating carbon catabolism repression in Aspergillus Nidulans (CreA).

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 1999. , 68 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 492
Keyword [en]
Physics, Molecular Dynamics simulation, Zif268, zinc fingers, GROMOS, linkers, recognition sites
Keyword [sv]
Fysik
National Category
Physical Sciences
Research subject
Physical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-396ISBN: 91-554-4592-6 (print)OAI: oai:DiVA.org:uu-396DiVA: diva2:163956
Public defence
1999-12-02, Kemikums föreläsningssal 4040, Uppsala universitet, Uppsala, 10:15
Available from: 1999-11-11 Created: 1999-11-11Bibliographically approved

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