Abstract：

In my talk, we will discuss our applications of different computational approaches to study proteins in biological systems. We will first show how molecular dynamic (MD) simulations with QM/MM potentials can be applied to understand catalytic mechanisms of enzymes. The early development of the QM/MM approach has led to the Nobel Prize in Chemistry to Karplus, Levitt and Warshel in 2013. A number of enzymes that have been investigated in our lab will be discussed, and one of our key questions is to understand substrate specificity of the enzymes. Serine-carboxyl peptidases (sedolisins) are one family of the enzymes we have studied. The members of this family also include tripeptidyl-peptidase (TPP1) for which the loss of the activity as a result of mutations in the TPP1 gene is the cause of one of the most common devastating neurodegenerative disorders of childhood. The enzymes to be discussed also include certain esterases and SAM-dependent methyltransferases (such as protein lysine and arginine methyltransferases and several members of the SABATH enzyme family), and some of them are the targets for drug design. The importance of substrate-assisted catalysis for substrate specificity is also suggested based on the results of the computational investigations. Our recent efforts in collaboration with plant biologists in using the tools of protein structure prediction to understand proteins and their function will be discussed as well. Finally, a new approach developed by our lab that can make identification, interpretation and extraction of biological insights from proteomes easier will be mentioned.