The overarching goal of this project is to elucidate the working mechanisms of peroxiredoxins and protein tyrosine kinases. The two protein systems have been extensively studied by the PI lab during the last several years, in which the computational resources provided by SNIC were essential. In this allocation period, we will focus on protein tyrosine kinases and a small enzyme, adenylate kinase, through a combination of the state-of-the-art quantum mechanical (QM) and molecular mechanical (MM) methods and molecular dynamics (MD) simulations. This research has a high relevance to human health and diseases, such as cancer, and has a great premise in the development therapies directed against kinases.
Protein tyrosine kinases are essential components in cell signaling that perform targeted phosphorylation on protein substrates to impact cell function. Our current focuses are on the catalytic and allosteric mechanisms of insulin receptor kinase (IRK). With the support of HPC2N, we have gathered a substantial evidence showing the important connection between slow protein dynamics and catalysis of IRK. During this allocation, we will continue the study to elucidate the role of slow protein dynamics in the allosteric mechanism of this kinase, by combining the targeted molecular dynamics with the string method. The combined approach will allow for efficient exploration of kinase conformational change pathways and determination of the free energy along the determined pathways. Comprehensive elucidation of the mechanisms would require multi-year efforts, in which continued support of HPC2N is essential.
In parallel, the catalytic mechanism of adenylate kinase (AK) will be investigated by applying the QM/MM simulation methods, which were developed by the PI lab. AK is an essential enzyme in the cell, catalyzing the reversible reaction between ATP+AMP and 2ADP. In collaboration with Prof. Magnus Wolf-Watz (Department of Chemistry, Umeå University), a world-reading NMR expert studying protein dynamics and catalysis, we have discovered that several catalytic residues in the active site play a key role in the modulation of the relative stability of the reactant versus product and fine-tune its catalytic activity. In this allocation, we will investigate the impact of these residue mutations on the catalytic mechanism of AK and compare the results with experimentally measured data. This study will be complemented with long classical MD simulations performed at the reactant and product states for the wild-type, as well as for all catalytic mutants.
Last, the PI lab has been actively developing accelerated QM/MM simulation methods, including the multi-scale ab initio QM/MM method and parallel semiempirical QM/MM method. During the coming allocation period, we will continue the development for better scalability of the developed QM/MM methods.