Lipid–protein forces predict conformational changes in a mechanosensitive channel

The mechanosensitive TREK-2 potassium channel, a member of the K2P family, has essential physiological roles and is, therefore, a pharmaceutical target. A combination of experimental and computational studies have established that of the two known conformations, “up” and “down”, membrane tension directly favors the “up” state, which displays a higher conductance. However, these studies did not reveal the exact mechanism by which the membrane affects the channel conformation. In this work, we show that changes in protein–lipid interaction patterns suffice in predicting this conformational change, and pinpoint potentially important residues involved in this phenomenon

Visualization of the mechanosensitive ion channel MscS under membrane tension

Mechanosensitive channels sense mechanical forces in cell membranes and underlie many biological sensing processes. However, how exactly they sense mechanical force remains under investigation. The bacterial mechanosensitive channel of small conductance, MscS, is one of the most extensively studied mechanosensitive channels, but how it is regulated by membrane tension remains unclear, even though the structures are known for its open and closed states. Here we used cryo-electron microscopy to determine the structure of MscS in different membrane environments, including one that mimics a membrane under tension. We present the structures of MscS in the subconducting and desensitized states, and demonstrate that the conformation of MscS in a lipid bilayer in the open state is dynamic. Several associated lipids have distinct roles in MscS mechanosensation. Pore lipids are necessary to prevent ion conduction in the closed state. Gatekeeper lipids stabilize the closed conformation and dissociate with membrane tension, allowing the channel to open. Pocket lipids in a solvent-exposed pocket between subunits are pulled out under sustained tension, allowing the channel to transition to the subconducting state and then to the desensitized state. Our results provide a mechanistic underpinning and expand on the ‘force-from-lipids’ model for MscS mechanosensation

Electronic charge and spin density distribution in a quantum ring with spin-orbit and Coulomb interactions

Charge and spin density distributions are studied within a nano-ring structure endowed with Rashba and Dresselhaus spin orbit coupling (SOI). For a small number of interacting electrons, in the presence of an external magnetic field, the energy spectrum of the system is calculated through an exact numerical diagonalization procedure. The eigenstates thus determined are used to estimate the charge and spin densities around the ring. We find that when more than two electrons are considered, the charge-density deformations induced by SOI are dramatically flattened by the Coulomb repulsion, while the spin density ones are amplified.Comment: 7 pages, 7 figure

Cutting the Gordian knot of excited-state modeling in complex environments

Autofluorescent proteins are a class of photoactive proteins widely used in biological experiments, being compatible with noninvasive imaging in living cells. The focus of this thesis is to develop a reliable and accurate modeling framework for the photophysical properties of these and other photosensitive biosystems. To this end, a multiscale approach is necessary given the size of the systems: A protein contains thousands of atoms and a quantum mechanical treatment thereof is clearly impossible. The light absorption and electronic excitation of these proteins is however typically localized on the so-called chromophore (or antenna) and a quantum description of this limited area combined with a less accurate but faster treatment of the rest of the protein is a possible solution. In this thesis, we propose a new multiscale scheme where the environment is still treated quantum mechanically but through the computationally cheaper density functional theory (DFT), and allowed to respond to the excitation of the embedded chromophore. This scheme is demonstrated on several small molecules and shown to improve on the use of a unresponsive environment.\ud We also present its application to a prototypical autofluorescent protein and pinpoint the important ingredients for a successful modeling of the photoexcitation in this coupled chromophore-protein complex