**Acknowledgements**

*Homology Molecular Modeling - Perspectives and Applications*

Hence, relative binding energy calculations further support all other MD simulation results highlighting the tight binding of TauR2 to the βIII/α/βIII tubulin isotype which is predominantly expressed in the neuronal cells and brain.

*The H12 and C-terminal tail regions show highest energy contribution for the binding of TauR2 in 6CVN\*,*  β*I/*α*/*β*I,* β*IIb/*α*/*β*IIb and* β*III/*α*/*β*III tubulin subunits except in case of 6CVN which does not have C-terminal* 

MTs are distributed across all types of cells and play an important role in the cellular functions. Structurally MTs are made up of α/β heterodimeric subunits. Large diversity of α and β-tubulin isotypes exists which are differently expressed in different types of cells, this makes MTs unique from one another in relative proportion of isotypes. The much elevated expression levels of βII and βIII tubulin isotypes about 58% and 25% respectively have been reported to in neuronal cells and brain [35]. The present study extensively uses molecular modeling approaches including homology modeling, MD simulation, binding energy to investigate the binding

Extensive analysis on MD simulation trajectory shows a stable complex formation in between different tubulin isotype and TauR2. The stability of these complexes is mainly mediated by the interactions of H12 helix and C-terminal tail of the α/β tubulin isotypes with TauR2. TauR2 shows differential binding affinity towards various neuronal specific β-tubulin isotypes (βI, βII and βIII) the order of binding affinity is 'βIII> βIIb>βI'. Thus, it is found that TauR2 expresses greater binding affinity with βIII and βIIb tubulin isotypes which are abundantly expressed in neuronal cells and brain. The molecular modeling strategy adopted in this chapter could be potentially used to understand differential binding affinity of other tau repeats such as R1, R3, R4 towards β tubulin isotypes present in other cell lines. The structures for other repeats could be generated using homology modeling and their interactions with neuronal specific tubulin isotypes could also be studied using similar molecular modeling approach.

mode and interaction of neuronal specific tubulin isotypes with TauR2.

**90**

**4. Conclusion**

**Figure 13.**

*tail region.*

VVB is thankful to IIT Bombay for Institute postdoctoral fellowship. Author is also thankful to Prof. Ambarish Kunwar, Department of Biosciences and Bioengineering, IIT Bombay, Mumbai for fruitful discussion and providing necessary computational resources to perform this research work. Author also sincerely thanks Creative Commons license for giving permission to use data from my manuscript my published research article in Scientific Reports (https://doi.org/10.1038/ s41598-019-47249-7). A copy of creative commons license can be found at the link http://creativecommons.org/licenses/by/4.0/

### **Conflict of interest**

The author declares no conflict of interest.
