Title:	Hybrid QM/MM modeling of molecular probes for medical diagnosis applications
DNr:	SNIC 2013/1-75
Project Type:	SNIC Medium Compute
Principal Investigator:	Murugan Natarajan Arul <murugan@kth.se>
Affiliation:	Kungliga Tekniska högskolan
Duration:	2014-01-01 – 2015-01-01
Classification:	10407 10402 10403
Homepage:	http://www.theochem.kth.se/people/murugan/
Keywords:

Abstract

The proposal aims to model and design the molecular probes using hybrid QM/MM approaches. In particular, molecular probes are useful in the medical diagnosis applications. Diseases in human-beings can be diagnosed in the early stages by monitoring (i) intracellular pH, (ii) aberrant expression of specific proteins (iii) ionic concentrations and (iv) the population of misfolded proteins. Optical probes which are sensitive to metals, pH change, and have tendency to bind to specific DNA sequence, membrane or bio-structures like fibrils can be used for this purpose. The nature of microenvironment in biostructure can be followed from fluorescence microscopy, if the probes have binding affinity to the biostructure along with the characteristic absorption or emission spectra in their bound state. Eventhough there exist considerable number of molecular probes for different diagnosis applications, the actual mechanism of the probes is often lacking. However, such insight into the mechanism based on microscopic details and structure-property relationships of the probes can be obtained through modelling and the knowledge gained can be eventually used for designing novel molecular probes for specific applications. The proposal aims to contributes to this subject to understand the working mechanism of pH probes, DNA, membrane, fibril and metal probes using an integrated approach involving molecular docking, molecular dynamics and Car-Parrinello hybrid QM/MM molecular dynamics. Eventually, the one photon and two photon absorption properties of molecular probes in the explicitly included solvent or bio-environment will be computed from hybrid QM/MM response approach as implemented in DALTON software. Using such an integrated approach, we have been able to model the mechanism of solvent polarity dependent absorption spectra of number of optical probes in solvent. Later we have demonstrated the modeling optical properties probes in the protein cavities (of BLG protein) and in their metal and fibril, membrane bound states. We show that such integrated approaches are the potential tools to model the optical properties of various molecular probes. In future, the investigations will be devoted to (i) the carbazole based extrinsic probes for DNA imaging and (ii) intrinsic probes such as green fluorescent proteins (GFPs) for pH sensing. The focus will be to understand the binding mechanism of carbazole probes into DNA and to study the DNA-induced changes in the structure and optical property of carbazoles. In the case of GFPs, the aim will be study the influence of mutations on the one and two photon absorption properties of their chromophores. The favourable mutations that are relevant for optical imaging applications of GFPs will be identified.