The proposal aims to design diagnostic agents for various diseases in human using multiscale modeling approaches involving molecular docking, molecular dynamics, ab initio molecular dynamics and hybrid QM/MM response calculations. Diseases in human-beings can be diagnosed in the early stages by monitoring (i) aberrant expression of specific proteins (ii) the population of misfolded proteins such as amyloid beta, tau, synuclein fibrils (iii) ionic concentrations and (iv) intracellular and extracellular pH,. There exist a number of molecular probes which are sensitive to metals, pH change, and have tendency to bind to specific DNA sequence, membrane or bio-structures like fibrils which can be used for this purpose. However for using them as diagnostic agents within human body many properties such as target specificity, bioavailability and non-toxicity have to be fulfilled. In-silico tools can be often useful to understand the working mechanism of molecular probes.
In this proposal we aim to study various molecular probes and to establish structure-property relationships in them which further can be used to design novel molecular probes. The integrated computational approaches will be employed to model different aspects of molecular probes and bio-structure complex system. Due to the simplicity and ability to sense the deep body organs, our focus will be to study only one and two photon probes for diagnostic applications. In particular, the structure and dynamics of the complex and the one and two photon properties of the molecular probe in presence of the explicitly treated bio-environment will be studied. Overall, the proposal aims 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. Further 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.
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. Recently we have demonstrated about modeling the optical properties probes in fibril-like and protein environments (of amyloid beta fibril and Beta lacto globulin) 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.