Adenylyl cyclase (AC) is an important messenger involved in G-protein-coupled-receptor signal transduction pathways, which is a well-known target for drug development. AC is regulated by activated stimulatory (Gαs) and inhibitory (Gαi) G proteins in the cytosol. Although experimental studies have shown that these Gα subunits can stimulate or inhibit AC’s function in a non-competitive way, it is not well understood what the difference is in their mode of action as both Gα subunits appear structurally very similar in a non-lipidated state. However, a significant difference between Gαs and Gαi is that while Gαs does not require any lipidation in order to stimulate AC, N-terminal myristoylation is crucial for Gαi’s inhibitory function as AC is not inhibited by non-myristoylated Gαi. At present, only the conformation of the complex including Gαs and AC has been resolved via X-ray crystallography. Therefore, understanding the interaction between Gαi and AC is important as it will provide more insight into the unknown mechanism of AC regulation. This study demonstrates via classical molecular dynamics simulations that the myristoylated Gαi1 structure is able to interact with apo adenylyl cyclase type 5 in a way that causes inhibition of the catalytic function of the enzyme, suggesting that Gα lipidation could play a crucial role in AC regulation and in regulating G protein function by affecting Gαi’s active conformation.

We present the results for CAPRI Round 50, the fourth joint CASP-CAPRI protein assembly prediction challenge. The Round comprised a total of twelve targets, including six dimers, three trimers, and three higher-order oligomers. Four of these were easy targets, for which good structural templates were available either for the full assembly, or for the main interfaces (of the higher-order oligomers). Eight were

G proteins are part of the G-protein-coupled receptor (GPCR) signal transduction cascade in which they transfer a signal from the membrane-embedded GPCR to other proteins in the cell. In the case of the inhibitory G-protein heterotrimer, permanent N-terminal myristoylation can transiently localize the Gα subunit at the membrane as well as crucially influence Gα's function in the GTP-bound conformation. The attachment of lipids to proteins is known to be essential for membrane trafficking; however, our results suggest that lipidation is also important for protein-protein interactions during signal transduction. Here we investigate the effect of myristoylation on the structure and dynamics of soluble Gα and its possible implication for signal transduction. A 2 μs classical molecular dynamics simulation of a myristoylated Gα-GTP complex suggests that the myristoyl-induced conformational changes of the switch II and alpha helical domains create new possibilities for protein-protein interactions and emphasize the importance of permanent lipid attachment for the conformation and functional tunability of signaling proteins.

This review provides a comprehensive overview of the structural dynamics in topical gas- and condensed-phase systems on multiple length and time scales. Starting from vibrationally induced dissociation of small molecules in the gas phase, the question of vibrational and internal energy redistribution through conformational dynamics is further developed by considering coupled electron/proton transfer in a model peptide over many orders of magnitude. The influence of the surrounding solvent is probed for electron transfer to the solvent in hydrated I−. Next, the dynamics of a modified PDZ domain over many time scales is analyzed following activation of a photoswitch. The hydration dynamics around halogenated amino acid side chains and their structural dynamics in proteins are relevant for iodinated TyrB26 insulin. Binding of nitric oxide to myoglobin is a process for which experimental and computational analyses have converged to a common view which connects rebinding time scales and the underlying dynamics. Finally, rhodopsin is a paradigmatic system for multiple length- and time-scale processes for which experimental and computational methods provide valuable insights into the functional dynamics. The systems discussed here highlight that for a comprehensive understanding of how structure, flexibility, energetics, and dynamics contribute to functional dynamics, experimental studies in multiple wavelength regions and computational studies including quantum, classical, and more coarse grained levels are required.

Hv1s are ubiquitous highly selective voltage-gated proton channels involved in male fertility, immunology, and the invasiveness of certain forms of breast cancer. The mechanism of proton extrusion in Hv1 is not yet understood, while it constitutes the first step toward the design of high-affinity drugs aimed at this important pharmacological target. In this contribution, we explore the details of the mechanism via an integrative approach, using classical and QM/MM molecular dynamics simulations of a monomeric hHv1 model. We propose that protons localize in three binding sites along the channel lumen, formed by three pairs of conserved negatively charged residues lining the pore: D174/E153, D112/D185, and E119/D123. Local rearrangements, involving notably a dihedral transition of F150, a conserved phenylalanine lining the permeation pathway, appear to allow protons to hop from one acidic residue to the next through a bridging water molecule. These results constitute a first attempt at rationalizing hHv1 selectivity for H and the role played by D112 in this process. They pave the way for further quantitative characterization of H transport in hHv1.