Conformational changes of proteins often play a key role in biological processes. However, they are sometimes difficult to infer from experimental data alone, and computations can shed important light on such phenomena. Dynein adaptors such as Bicaudal D2 (BicD2) recognize cargo in the cell for transport and link it to the motor complex. BicD2-dependent transport events are important for brain and muscle development, and human disease mutations cause spinal muscular atrophy. However, a fundamental understanding of BicD2 function remains elusive. Molecular dynamics simulations of BicD2 indicate that it can undergo coiled coil registry switches. In addition to the homotypic registry in the experimental crystal structure, an asymmetric registry is also stable, and the conformation of a pair of Phe residues (F743) plays a key role in stabilizing one registry over the other. Simulations of the R747C human disease variant show a spontaneous local coiled coil registry switch depending on the conformation of F743. A spontaneous registry shift is also observed for the F743I mutant, which increases dynein recruitment in the <i>Drosophila</i> homolog. Our results suggest that the ability to undergo registry switches may be an inherent property of coiled coil structures, which may occur more frequently than currently assumed.<br/><br/>Conformational changes of the calcium-sensing protein calmodulin (CaM) depending on the number of bound calcium ions modify its interactions with various target proteins, leading to mediation of many crucial processes such as metabolism, apoptosis and smooth muscle contraction. Photoregulation of these processes can be achieved by functionalizing CaM with bistable molecular photoswitches. Recent experimental studies functionalized seven sites in CaM with an azobenzene derivative, the latter acting as a photoswitch. Photocontrol of CaM binding with the M13 peptide (a fragment of skeletal muscle myosin light chain kinase) was observed for three of these seven sites located near the calcium-binding site and the peptide-binding site. Insights obtained from simulations into the different behaviors of these mutants will be discussed, and new functionalization sites will be proposed.

Role of protein conformational changes in cellular cargo transport and calcium signaling

2019 Spring National Meeting

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