Molecular mechanism of CRISPR systems
CRISPR-Cas9 is a revolutionary genome editing tool, which enables to easily manipulate nucleic acids. Our labs uses computational methods to unravel the function and improve biological applications of CRISPR genome-editing machineries. We have disclosed the mechanism of RNA binding and the association with the nucleic acids, delivering also the molecular details of off-target effects. We revealed an intriguing mechanism of allosteric regulation and we recently disclosed the catalytic state of the system, prone to perform genome editing.
- J. Chem. Inf. Model. 2019, In press
- ACS Cent. Sci. 2019, 5, 651-662.
- Q. Rev. Biophys. 2018, 51, e9.
- J. Am. Chem. Soc. 2017, 139, pp. 16028–16031.
- Proc. Natl. Acad. Sci. USA, 2017, 114, pp. 7260–7265.
- ACS Cent. Sci. 2016, 2, pp. 756–763.
Non-coding RNA function & dynamics
RNA is a fundamental molecule that codes for protein and controls gene expression, playing a key regulation role in many cell responses and vital processes, such as human genetic heritance and diseases. We are interested in clarifying the molecular basis of non-coding RNA, which regulates gene expression via a variety of yet unknown mechanisms. We have suggested a mechanism for the splicing reaction in the bacterial groupII intron, and studied the functional dynamics of the human splicesome.
- J. Struct. Biol. 2019, 206, 267-279.
- Proc. Natl. Acad. Sci. USA 2018, 115, 6584-6589.
- J. Am. Chem. Soc. 2016, 138, 10374–10377
- J. Chem. Theory Comput. 2017, 13, 340–352
As originally revealed by Steitz & Steitz (PNAS 1993, 90), DNA/RNA endonucleases perform phosphodiester bond cleavage via a two-metal-ion aided mechanism. We are using computational methods to clarify the two-metal aided mechanism in several endonucleases. Our specific interest in understanding the role of metal ions and the functional differences in the catalysis of RNA & DNA.
- Acc. Chem. Res. 2015, 48, pp 220–228
- J. Chem. Theory Comput. 2013, 9, pp 857–862
- Chem. Commun. 2015, 51, pp 14310-13
Nucleosome dynamics & chromatin drug development
The constituents of chromatin, chromosomal DNA and histone proteins, are key molecular targets for anticancer drugs. By integrating molecular dynamics with X-ray crystallography and biochemical assays, we have characterized the mechanism of action of promising metal-based anticancer agents at the level of the nucleosome core particle, the fundamental unit of chromatin. This integrated research deciphered the corresponding relationships to cytotoxicity and impact on cancer cell function.