Emeritus Group, Physical Biochemistry
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One of the traditional areas of the department´s work is concerned with the development and application of derivatives of natural products as tools for molecular biological, biochemical, biophysical and cell biological purposes. In my own earlier work (Roger Goody), this was mainly with nucleotide derivatives, and while there is still an interest in this area, it has been largely replaced by activities in the area of synthetic and semisynthetic proteins, and there are many examples of the use of these methods in the work of the groups in the department. In this area, there is an important collaboration with Department IV, particularly on the subject of posttranslational modification by lipid molecules.
Advances in peptide chemistry and biochemistry have reached a stage in which the ideal of being able to modify a protein in a specific manner at any position in its sequence is becoming realistic. This was previously only possible using site-directed mutagenesis, with the limitation that only natural aminoacids can be used unless extremely complex procedures leading to very low yields of products are used. Small proteins can now be generated by total synthesis, and the introduction of the so-called in vitro ligation method a few years ago essentially doubles the size of proteins which can be generated by total synthesis. The second important development comes from the exploitation of intein biochemistry/chemistry, since the product of intein activity has a reactive C-terminus which can be used to ligate a peptide, which can be a large synthetic peptide of up to ca. 100 aminoacids, to generate a C-terminal region in which each position can contain any conceivable modification which can tolerate the conditions of synthesis and removal of protecting groups. Alternatively, an N-terminal peptide of up to ca. 100 residues can be prepared chemically with an activated C-terminus which can be ligated with an expressed C-terminal region containing a cysteine at its N-terminus. The combination of these strategies allows a great deal of flexibility with respect to the modifications which can be introduced, and this includes backbone chemistry which differs from natural peptide chemistry. Specific examples of these approaches are given in the descriptions of the work of the Alexandrov, Becker, Engelhard and Rak groups.