A mechanism for agonist activation of the glucagon-like peptide-1 (GLP-1) receptor through modelling & molecular dynamics

The receptor for glucagon-like peptide 1 (GLP-1R) is a validated drug target for the treatment of type 2 diabetes and obesity. Recently the first three structures of GLP-1R were published – an X-ray structure of the apo transmembrane domain in the inactive conformation; an X-ray structure of the full-length receptor bound to a truncated peptide agonist; and a cryo-EM structure of the full-length receptor bound with GLP-1 and coupled to the G protein Gs. Since the inactive structure was incomplete, and the two active-state structures shared significant differences, we utilised all available knowledge to build hybrid models of the full length active and inactive state receptors. The two models were simulated using molecular dynamics and the output trajectories analysed and compared to reveal insights into the mechanism for agonist-mediated receptor activation. His-7, Glu-9 and Asp-15 of GLP-1 act together to destabilise transmembrane helix 6 and extracellular loop 3 in order to generate an active conformation of GLP-1R

Concentration Dependent Ion Selectivity in VDAC: A Molecular Dynamics Simulation Study

The voltage-dependent anion channel (VDAC) forms the major pore in the outer mitochondrial membrane. Its high conducting open state features a moderate anion selectivity. There is some evidence indicating that the electrophysiological properties of VDAC vary with the salt concentration. Using a theoretical approach the molecular basis for this concentration dependence was investigated. Molecular dynamics simulations and continuum electrostatic calculations performed on the mouse VDAC1 isoform clearly demonstrate that the distribution of fixed charges in the channel creates an electric field, which determines the anion preference of VDAC at low salt concentration. Increasing the salt concentration in the bulk results in a higher concentration of ions in the VDAC wide pore. This event induces a large electrostatic screening of the charged residues promoting a less anion selective channel. Residues that are responsible for the electrostatic pattern of the channel were identified using the molecular dynamics trajectories. Some of these residues are found to be conserved suggesting that ion permeation between different VDAC species occurs through a common mechanism. This inference is buttressed by electrophysiological experiments performed on bean VDAC32 protein akin to mouse VDAC

Outer membrane protein folding from an energy landscape perspective

The cell envelope is essential for the survival of Gram-negative bacteria. This specialised membrane is densely packed with outer membrane proteins (OMPs), which perform a variety of functions. How OMPs fold into this crowded environment remains an open question. Here, we review current knowledge about OFMP folding mechanisms in vitro and discuss how the need to fold to a stable native state has shaped their folding energy landscapes. We also highlight the role of chaperones and the β-barrel assembly machinery (BAM) in assisting OMP folding in vivo and discuss proposed mechanisms by which this fascinating machinery may catalyse OMP folding

Comparative Molecular Dynamics Simulation Studies of Realistic Eukaryotic, Prokaryotic, and Archaeal Membranes

We present a comparative all-atom molecular dynamics simulation study of 18 biomembrane systems with lipid compositions corresponding to eukaryotic, bacterial, and archaebacterial membranes together with three single-component lipid bilayers. A total of 105 lipid types used in this study include diverse sterols and glycerol-based lipids with acyl chains of various lengths, unsaturation degrees, and branched or cyclic moieties. Our comparative analysis provides deeper insight into the influences of sterols and lipid unsaturation on the structural and mechanical properties of these biomembranes, including water permeation into the membrane hydrocarbon core. For sterol-containing membranes, sterol fraction is correlated with the membrane thickness, the area compressibility modulus, and lipid order but anticorrelated with the area per lipid and sterol tilt angles. Similarly, for all 18 biomembranes, lipid order is correlated with the membrane thickness and area compressibility modulus. Sterols and lipid unsaturation produce opposite effects on membrane thickness, but only sterols influence water permeation into the membrane. All membrane systems are accessible for public use in CHARMM-GUI Archive. They can be used as templates to expedite future modeling of realistic cell membranes with transmembrane and peripheral membrane proteins to study their structure, dynamics, molecular interactions, and function in a nativelike membrane environment.http://deepblue.lib.umich.edu/bitstream/2027.42/171945/2/acs.jcim.1c01514.pdfPublished versio