Wilhelmsson research group

Research group leader: Associate Professor Marcus Wilhelmsson


PhD students Moa Sandberg Wranne and Sangamesh Sarangamath

PhD student Mattias Bood (together with Morten Grøtli GU and AstraZeneca, Mölndal)

PostDoc Anders Foller Larsen (collaboration with AstraZeneca, Mölndal)


 

Research

The group develops molecules that can be used to replace the natural DNA/RNA building blocks, the bases, and unlike the bases, which are transparent, has properties that make them fluorescent (emit light) when they are hit by light of the correct colour (300-500 nm). These so called fluorescent base analogues (see review by Wilhelmsson in QRB 2010) have molecular properties that are optimal for being inserted into the natural DNA/RNA structure (Figure 1). They can therefore be used to, on a very detailed level, understand more about essential processes in cells like replication, during cell division, and transcription, during protein synthesis. Fundamental knowledge thereof is vital in order to comprehend cellular processes and errors that could occur and cause several common diseases.

 

 
Figure 1. Left: Fluorescent base analogue tC, right, base-pairing with the natural base guanine, left. In the figure we look down the long-axis of a natural DNA duplex. Right: Same base analogue instead looking along the short-axis of the DNA duplex.
 

One of the goals is to design and construct new fluorescent base analogues that can replace all the natural bases. This is done by trying to predict structural and spectral properties with the help of quantum chemical methods where after promising candidates are synthesized. Parts of this work is performed in collaboration with Associate Professor Morten Grøtli  at Göteborgs Universitet. After the synthesis, the new base analogues are investigated to determine whether they have promising  fluorescent properties, where after interesting ones are incorporated into DNA/RNA (often in collaboration with Professor Tom Brown, Oxford, UK) for further characterization. The characterization is performed to understand how well the fluorescent base analogue works as a replacement for a natural base, it should not perturb the properties or structure of the DNA/RNA, as well as to establish its spectral and photophysical properties for further use in biochemically and biologically relevant investigations.

 

Another goal is to use the novel fluorescent base analogues, to make them available for other researchers as well as to develop biochemical/biophysical/biological methods where the probes can be used.  An example thereof is the freeware FRETmatrix that has been developed by the group and can be used to obtain detailed structural information about biomolecules (DNA/RNA and molecules that interact with these). The investigations that can be performed using FRETmatrix have been enabled thanks to a newly developed FRET-pair that constitutes a unique tool to measure short distances in biomolecular systems (Figure 2). The FRET-pair is the first of its kind and was published by the group in JACS 2009. This FRET-pair is now being used by the group in several studies one of which has already been published in PNAS 2012. The base analogues are also used to study among other things polymerases (NAR 2009, Biochemistry 2009), cellular molecules that are central at cell division and protein expression. 


Figure 2. Figure shows how the FRET-pair consisting of two base analogues, tCO-tCnitro, developed by our group at the same time can be used for obtaining distance and orientation information. Red squares show measured steady-state fluorescence values and blue dots the corresponding time-resolved data. Measurements performed using the FRET-pair separated by 2-13 base pairs.
 

 

Several of the fluorescent molecules developed by the group are now distributed through a collaboration between the American company GlenResearch Corp., world leading in chemicals related to DNA/RNA, and ModyBase HB, a company founded by Marcus Wilhelmsson.

 

The group has or has earlier received grants from among other these sources:

The Swedish Research Council (VR)

Olle Engkvist Byggmästare Foundation

Kristina Stenborg’s Foundation

Chalmers Area of Advance Nanoscience and Nanotechnology

Linneaus grant from the Swedish Research Council to the SUPRA project

SSF (Swedish Foundation for Strategic Research)


 


Similar information in Swedish.

Published: Sun 17 Mar 2013. Modified: Thu 10 Sep 2015