The overarching goal of the 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 continue to study 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. Due to the importance of kinases in human health and cancer, the understanding of their molecular mechanisms is of fundamental importance in biology and has a greats premise in the development therapies directed against kinases.
Protein tyrosine kinases are essential components in cell signaling that perform targeted phosphorylation of protein substrates to make impacts on cell function. Our current focuses are on the catalytic and allosteric mechanisms of insulin receptor kinase (IRK) and anaplastic lymphoma kinase (ALK). Recently, we have shown that protein dynamics play a crucial role in their catalytic and allosteric mechanisms. In the coming allocation period, we will continue the study to deepen our understanding of the roles of protein dynamics in the conformational change of IRK, by combining the targeted molecular dynamics with the string method. It is expected that the combined approach allows the efficient exploration of the conformational change pathways of the kinase and the determination of the free energy along the determined pathways. For ALK, long classical MD simulations will be performed to establish the characters of its structure and shed lights on the structure of ALK in its fully phosphorylated, thus activated, state, whose experimental structure is unknown.
In parallel, we will investigate the catalytic mechanism of adenylate kinase (AK). AK is an essential enzyme in the cell, maintaining a balance between the intracellular ATP and ADP by catalyzing the reversible reaction between ATP+AMP and 2ADP. In collaboration with Prof. Magnus Wolf-Watz (Department of Chemistry, Umeå University), who is a world-reading NMR expert studying protein dynamics and catalysis, we have found that several catalytic residues, e.g., Lys13 and Arg167, play a key role in modulating the relative stability of the reactant versus product and fine-tune its catalytic activity. In this allocation period, we will apply the QM/MM simulation methods, which were developed by the PI lab, to determine the catalytic mechanism of AK and further understand the mechanistic underpinning of these residues. This study will be complemented by long classical MD simulations performed at the reactant and product states for the wild-type as well as 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.