Protein Association Involving Intrinsic Disordered Proteins and Its Regulation on Synaptic Plasticity through Modulating CA2+ Binding
Zhang, Pengzhi 1988-
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Protein-protein association is essential for biological functions in all living organisms, including synaptic plasticity that relates to learning and memory formation, which involves the regulation of Ca2+ signals. The ubiquitin Ca2+ signaling protein calmodulin (CaM) plays a central role in encoding Ca2+ signals by interacting with a diversity of CaM binding target proteins (CaMBTs). Therefore, the mechanism of how CaM can recognize CaMBTs has aroused a broad and lasting interest. Experimental investigations on binding of CaM and CaMBTs uncover thermodynamic and kinetic properties of protein interactions but they lack molecular details to explain some macroscopic phenomena. Moreover, in many cases it is implausible to determine the molecular mechanisms. Analytical models usually use simplified models but overlook the structural flexibility of the proteins. In this study, firstly I implemented a sequence-based dihedral angle potential for capturing the characteristics of intrinsically disorder unstructured CaMBTs. By applying molecular simulations on association of CaM and CaMBTs, I revealed that molecular recognition requires mutual conformational changes of both CaM and CaMBT. Secondly, among the CaMBTs, CaM-dependent kinase II (CaMKII) and neurogranin (Ng) play an essential role in synaptic plasticity and they are experimentally shown to have opposing effects on Ca2+ affinity for CaM, but the molecular mechanism is unknown. Advancing coarse-grained molecular simulations employing the model, I found that the interaction between Ng peptide and the C-domain of CaM (cCaM) disrupts the intra-molecular interaction between the two Ca2+ binding loops. Next, I performed steered molecular dynamics simulations on atomistic models from several reconstructed coarse-grained structures to compute the changes in Ca2+ affinity for CaM with and without Ng peptide using Jarzynski’s equality. I discovered the molecular underpinnings of lowered affinity of Ca2+ for CaM in the presence of Ng peptide by showing that the N-terminal acidic region of Ng pries open the β-sheet structure between the Ca2+ binding loops at cCaM, enabling Ca2+ release. In contrast, CaMKII increases Ca2+ affinity for cCaM by stabilizing them. This study allows opportunities to connecting the molecular regulations in atomistic detail to the understanding of cellular process cascade of learning and memory formation.