Chemometrics

In one of the most intriguing examples of biological wizardry, in every cell, every second, thousands of proteins self-pack into the unique shapes that hold the key to their function. In essence, a freshly-formed chain of amino acids bends, loops, twists, coils and collapses on itself to produce the finished design. We know that these rearrangements are determined by chemical attractions between the amino acids. But in stark contrast to our knowledge of the digital precision by which DNA codes the sequence of amino acids, the chemical forces that direct folding act in an incompletely understood, nebulous way, much as the weather is ruled by physical processes. A predictive model for protein structure remains one of science’s holiest grails, promising incredible benefits throughout the biomedical sciences. In our lab the quest is focused on observations of real instances of protein folding, unfolding and misfolding, a complementary and ground-truthing approach to algorithm-based models.

Maintenance of life requires the preservation of genomic integrity. Double-strand breaks (DSBs) are a particularly lethal form of DNA damage and incorrectly repaired or unrepaired DSBs can lead to mutations, loss of genetic information and even cell death. Cells in all domains of life are capable of faithful DSB repair via homologous recombination, which requires an unbroken, homologous copy of DNA as template for repair. Apart from recombination, eukaryotes and some bacteria also use an alternative end-joining pathway, which does not require a second copy of duplex DNA for repair. Although error-prone, this pathway avoids the lethality of a DSB, making it important. While extensive biochemical experiments have been useful in understanding the key events underlying DSB repair in vitro, how repair is facilitated in vivo remains poorly understood. Recent advances in molecular and cellular biology techniques have now opened the doors to studying mechanisms of repair and the regulation of this process in living cells. This is particularly important, as repair has to be coordinated with other cellular processes such as DNA replication and cell division as well as carried out under the constraint of chromosome structure.
The goal of my research group is to understand how DNA repair pathways are regulated to ensure the maintenance of genomic integrity.

We are always looking for motivated people to join our lab! The questions we ask are inter-disciplinary in nature and we are happy to have researchers from diverse backgrounds of science working together. Do get in touch if you are interested in questions pertaining to the maintenance of genome integrity in cells.

Genome sequencing projects have enormous potential for benefiting human endeavors. However, just as acquiring a language’s vocabulary does not enable one to speak it, databases that list the amino acid composition of proteins do not directly tell us much about these proteins’ higher-level structure and function. The most productive way to indirectly exploit these databases has been to start with the small number of proteins that are fully-characterised and to assume that other “similar” proteins will have a related structure and function. Proteins with very similar amino acid sequence are “no-brainers”, but the real test, which our group largely focuses on, is to detect the “essential” similarity in proteins whose non-critical sections have experienced random rearrangements during evolution. In such cases functionally similar proteins may have less than 25% sequence overlap.

Our research focuses on how things move across the membrane and how membrane proteins function. Using electron cryomicroscopy and X-ray crystallography, we aim to determine the structure and elucidate the function of a range of membrane proteins including enzymes and channels. In the near future, we would like to expand into imaging some of these proteins in their native cellular environment by electron cryotomography.
Misfolding of proteins can lead to accimulation of toxic aggregates. It is assumed that higher energy intermediates along the protein folding landscape seed the formation of toxic aggregates. Protein quality control systems like the Ubiquitin-proteasome pathway ensures that these potentially toxic species are degraded. We are interested to get insights into the structure of higher energy intermediates. We also investigate how misfolded proteins targeted by the ubiquitin-proteasome pathway.

Mojtaba graduated from the institute in 2018 with the supervision of Dr. Sarafraz Yazdi. Mojtaba specializes in the separation of pharmaceutical products and is currently researching proteomics as a visiting professor. Misfolding of proteins can lead to accimulation of toxic aggregates. It is assumed that higher energy intermediates along the protein folding landscape seed the formation of toxic aggregates. Protein quality control systems like the Ubiquitin-proteasome pathway ensures that these potentially toxic species are degraded. We are interested to get insights into the structure of higher energy intermediates. We also investigate how misfolded proteins targeted by the ubiquitin-proteasome pathway.