Biomolecular Architecture

The main topics of the Biomolecular Architecture group concern the structural study of short DNA fragments and proteins using X-ray diffraction techniques. Results are published in leading journals such as Journal of Molecular Biology, Acta Crystallographica D, Biochemistry, JACS, Nucleic Acids Research, Chemistry Eur. J., Nature and Science. 
 

The structure determination of biological macromolecules is one of the most promising developments in crystallography. In order to understand the biological function of DNA and proteins it is important to know its 3-dimensional structure at the atomic level.
 

Our research deals with the following topics: 

•  the incorporation of modified sugars in short DNA fragments, 

Antisense oligonucleotides can be considered as a new class of potential therapeutic reagents which prevent the synthesis of specific proteins, by a physical blockage of the translation process, or by an RNase H catalysed degradation of mRNA. The main obstacle for their use is their low metabolic stability. Recently it was shown that the stability can be increased by the incorporation of hexoses. The influence of this modification is studied by X-ray diffraction. Until now the structures of the double helical hexitol nucleic acid (HNA) and double helical cyclohexene nucleic acid (CeNA) fragments with sequence GTGTACAC have been determined. 

• non-Watson-Crick base pairing

Modified bases such as the pyrimidine analogues N4-methoxycytosine (M) and its bicyclic analogue 6H,8H-3,4-dihydropyrimido(4,5-c)(1,2)oxazin-7-on (P) are incorporated into DNA to verify its influence on the geometry and hydration. The crystal structure of d(CGCGPG) contains two P.G base pairs in a different form: a Watson-Crick pair (3 H-bonds) and a wobble pair (2 H-bonds) exist in the same double helix and illustrate the ambivalent and strong mutagenic character of the P base. 

• the interaction of anti-tumoral drugs in DNA, 

In a search for the specific recognition mechanisms of intercalating anti-tumoral compounds in DNA-drug complexes, the structures of an number of DNA-drug complexes, such as complexes of the B-DNA hexamer d(TGATCA) with daunomycin and nogalamycin were determined. 

Crystal engineering techniques are used to enhance the resolution of DNA-minor groove complexes, which in general do not diffract further than about 2.2A. 

•  the formation of triple helices, 

Nucleic acid triplexes are formed by sequence-specific interactions between single stranded polynucleotides and the double helix. These triplexes are implicated in genetic recombination in vivo and have implications to areas that include genome analysis and antigene therapy. Despite the importance of the triple helix, only limited high-resolution structural information is available. Crystal engineering techniques have allowed us to characterize triple helix motifs by using a double helical fragment with one or more overhanging bases. Depending on the crystal packing the overhanging bases interact with adjacent Watson-Crick base pairs resulting in the formation of triplets. Parameters derived from these triplets have made it possible to construct models of both parallel and antiparallel (G.GC)12 triple helices. 

• the study of B-DNA structures at atomic resolution. 

We have recently described the structure of a B-DNA fragment at atomic resolution (1.15A) with highly organised hydration patterns in both grooves. The narrow d(AATT) minor groove is occupied by an 'extended hydration spine' alternately bridging base pairs and phosphate O1P atoms of opposite strands. The unrestrained refinement of the daunomycin-d(CGCGCG) complex at 1.1A resolution suggests that the sugar phosphate backbone is considerably more conformationally flexible than was previously observed.  

The Laboratory is the Belgian National Affiliated Data Centre for the Cambridge Structural Database. Future academic users should contact Prof. Luc Van Meervelt. 

The Laboratory is part of the K.U.Leuven BioMacS consortium.

We also perform on demand single crystal structure determinations on small (organic, inorganic) molecules, and have facilities for molecular modelling and graphics. 

Copyright 1999-2011, Katholieke Universiteit Leuven
Page Design: Luc Van Meervelt
Information Provider: Department of Chemistry
Comments for the Author: Luc Van Meervelt