Characterizing allosteric mechanisms in multi-domain proteins with slow interconversion rates (on the order of seconds) remains a significant challenge for traditional computational methods. Here, I will present lessons we learnt from studying the tyrosine phosphatase SHP2, a key regulator of cellular signaling, whose activating mutations are associated with developmental disorders and multiple cancer types. SHP2 comprises two SH2 domains (NSH2 and C-SH2), followed by a catalytic PTP domain. The SH2 domains recognize and bind phosphotyrosine-containing sequences of SHP2 partners. In its inactive state, SHP2 adopts a closed conformation, with the N-SH2 domain occluding the catalytic site of the PTP domain. Activation involves SH2 domain engagement with phosphorylated partners, which induces structural rearrangements. However, the precise contribution of the SH2 domains to binding affinity and partner recruitment remains poorly understood. We will show how enhanced sampling techniques and coarse-grained molecular-dynamics simulations can reveal activation pathways and elucidate topological constraints arising from the binding of bis-phosphorylated peptides to both SH2 domains.
Calligari et al. (Sun,) studied this question.