Computational modelling of spleen tyrosine kinase (SYK) and its interaction with b-cell receptors

Abstract

Spleen Tyrosine Kinase (SYK) is a central non-receptor tyrosine kinase involved in B cell receptor (BCR) signalling, where its recruitment and activation are mediated through interactions with the immunoreceptor tyrosine-based activation motifs (ITAMs) of the CD79A and CD79B co-receptors. Although SYK has been extensively investigated as a therapeutic target, the molecular basis underlying its dynamic interaction with phosphorylated and unphosphorylated BCR co-receptors remains poorly understood. In this study, we employed all-atom Gaussian accelerated molecular dynamics (GaMD) simulations to investigate the conformational dynamics of SYK in complex with CD79A and CD79B ITAMs under different phosphorylation states. Four systems were constructed and simulated in explicit solvent: SYK bound to unphosphorylated and doubly phosphorylated forms of CD79A and CD79B. Each system was subjected to triplicate 1 μs GaMD simulations using the AMBER ff19SB and phosaa19SB force fields.