GROMACS Workshop October 2018

The 2018 workshop will provide opportunities for GROMACS developers and power-users to use or implement their own enhanced simulation protocols, involving for example fast multipole methods, constant pH, or experimental constraints from microscopy/spectroscopy. Key questions will include:

  • How can a highly optimized, parallel simulation code provide a general infrastructure that allows incorporation of new methods in a straightforward way?
  • Can it do so without sacrificing (parallel) performance?
  • Can the software be made less monolithic and blackbox-like, but more modular and extensible?
  • Can providing an own method become less of a challenge for the average scientist who is not at the same time a GROMACS coding expert?

To join us 17–19 October 2018 in Göttingen, visit the registration page today!

Thanks to sponsors BioExcel and SPPEXA, and to the Theoretical and Computational Biophysics group at the Max Planck Institute for Biophysical Chemistry for venue and other support.


Contact Line Friction in Dynamic Wetting

From the July 2018 release of Physical Review Fluids (v. 3, pp. 074201):

Molecular Origin of Contact Line Friction in Dynamic Wetting

Petter Johansson & Berk Hess

A hydrophilic liquid, such as water, forms hydrogen bonds with a hydrophilic substrate. The strength and locality of the hydrogen bonding interactions prohibit slip of the liquid over the substrate. The question then arises how the contact line can advance during wetting. Using large-scale molecular dynamics simulations we show that the contact line advances by single molecules moving ahead of the contact line through two distinct processes: either moving over or displacing other liquid molecules. In both processes friction occurs at the molecular scale. We measure the energy dissipation at the contact line and show that it is of the same magnitude as the dissipation in the bulk of a droplet. The friction increases significantly as the contact angle decreases, which suggests suggests thermal activation plays a role. We provide a simple model that is consistent with the observations.

Read the full publication here.


Frozen in Motion

From the June 1, 2018 release of eLife (v. 7 p. e36861):

Characterisation of Molecular Motions in Cryo-EM Single-Particle Data by Multi-Body Refinement in RELION

Takanori Nakane, Dari Kimanius, Erik Lindahl, & Sjors H.W. Scheres

Macromolecular complexes that exhibit continuous forms of structural flexibility pose a challenge for many existing tools in cryo-EM single-particle analysis. We describe a new tool, called multi-body refinement, which models flexible complexes as a user-defined number of rigid bodies that move independently from each other. Using separate focused refinements with iteratively improved partial signal subtraction, the new tool generates improved reconstructions for each of the defined bodies in a fully automated manner. Moreover, using principal component analysis on the relative orientations of the bodies over all particle images in the data set, we generate movies that describe the most important motions in the data. Our results on two test cases, a cytoplasmic ribosome from Plasmodium falciparum, and the spliceosomal B-complex from yeast, illustrate how multi-body refinement can be useful to gain unique insights into the structure and dynamics of large and flexible macromolecular complexes.

Read the full publication here.


Grattis till Dr Heusser

Members of Molecular Biophysics Stockholm joined family and friends in celebrating Stephanie Heusser’s successful defense of her PhD thesis, Allosteric Modulation of Pentameric Ligand-Gated Ion Channels by General Anesthetics, 4 May 2018 in Magnélisalen, Stockholm University. Professor Pierre-Jean Corringer (Pasteur Institute, Paris, France) served as opponent, and Professor Erik Lindahl (Stockholm University, KTH Royal Institute of Technology) led a toast to his advisee of four years.


Consciousness Crystallized

Featured on the April 24, 2018 cover of Cell Reports (v. 23 pp. 993–1004):

Structural Basis for a Bimodal Allosteric Mechanism of General Anesthetic Modulation in Pentameric Ligand-Gated Ion Channels

Zaineb Fourati*, Rebecca J. Howard*, Stephanie A. Heusser, Haidai Hu, Reinis R. Ruza, Ludovic Sauguet, Erik Lindahl**, & Marc Delarue**

*Equal contributions; **senior authors

Ion channel modulation by general anesthetics is a vital pharmacological process with implications for receptor biophysics and drug development. Functional studies have implicated conserved sites of both potentiation and inhibition in pentameric ligand-gated ion channels, but a detailed structural mechanism for these bimodal effects is lacking. The prokaryotic model protein GLIC recapitulates anesthetic modulation of human ion channels, and it is accessible to structure determination in both apparent open and closed states. Here, we report ten X-ray structures and electrophysiological characterization of GLIC variants in the presence and absence of general anesthetics, including the surgical agent propofol. We show that general anesthetics can allosterically favor closed channels by binding in the pore or favor open channels via various subsites in the transmembrane domain. Our results support an integrated, multi-site mechanism for allosteric modulation, and they provide atomic details of both potentiation and inhibition by one of the most common general anesthetics.

Read the full publication here.


Calmodulin Contortions

From the April 3, 2018 release of PLoS Computational Biology (v. 14 p. e1006072):

Effect of Ca²⁺ on the promiscuous target-protein binding of calmodulin

Annie M. Westerlund & Lucie Delemotte

Calmodulin (CaM) is a calcium sensing protein that regulates the function of a large number of proteins, thus playing a crucial part in many cell signaling pathways. CaM has the ability to bind more than 300 different target peptides in a Ca²⁺-dependent manner, mainly through the exposure of hydrophobic residues. How CaM can bind a large number of targets while retaining some selectivity is a fascinating open question. Here, we explore the mechanism of CaM selective promiscuity for selected target proteins. Analyzing enhanced sampling molecular dynamics simulations of Ca²⁺-bound and Ca²⁺-free CaM via spectral clustering has allowed us to identify distinct conformational states, characterized by interhelical angles, secondary structure determinants and the solvent exposure of specific residues. We searched for indicators of conformational selection by mapping solvent exposure of residues in these conformational states to contacts in structures of CaM/target peptide complexes. We thereby identified CaM states involved in various binding classes arranged along a depth binding gradient. Binding Ca²⁺ modifies the accessible hydrophobic surface of the two lobes and allows for deeper binding. Apo CaM indeed shows shallow binding involving predominantly polar and charged residues. Furthermore, binding to the C-terminal lobe of CaM appears selective and involves specific conformational states that can facilitate deep binding to target proteins, while binding to the N-terminal lobe appears to happen through a more flexible mechanism. Thus the long-ranged electrostatic interactions of the charged residues of the N-terminal lobe of CaM may initiate binding, while the short-ranged interactions of hydrophobic residues in the C-terminal lobe of CaM may account for selectivity. This work furthers our understanding of the mechanism of CaM binding and selectivity to different target proteins and paves the way towards a comprehensive model of CaM selectivity.

Read the full publication here.


Ceramide Simulations

Featured on the March 13, 2018 cover of Biophysical Journal (v. 114 pp. 1116–1127):

Structural Transitions in Ceramide Cubic Phases during Formation of the Human Skin Barrier

Christian L. Wennberg, Ali Narangifard, Magnus Lundborg, Lars Norlén, & Erik Lindahl

The stratum corneum is the outermost layer of human skin and the primary barrier toward the environment. The barrier function is maintained by stacked layers of saturated long-chain ceramides, free fatty acids, and cholesterol. This structure is formed through a reorganization of glycosylceramide-based bilayers with cubic-like symmetry into ceramide-based bilayers with stacked lamellar symmetry. The process is accompanied by deglycosylation of glycosylceramides and dehydration of the skin barrier lipid structure. Using coarse-grained molecular dynamics simulation, we show the effects of deglycosylation and dehydration on bilayers of human skin glycosylceramides and ceramides, folded in three dimensions with cubic (gyroid) symmetry. Deglycosylation of glycosylceramides destabilizes the cubic lipid bilayer phase and triggers a cubic-to-lamellar phase transition. Furthermore, subsequent dehydration of the deglycosylated lamellar ceramide system closes the remaining pores between adjacent lipid layers and locally induces a ceramide chain transformation from a hairpin-like to a splayed conformation.

Read the full publication here.


Biophysics in San Francisco

Eleven members of Molecular Biophysics Stockholm traveled to San Francisco, CA to present their research at the 62nd Annual Meeting of the Biophysical Society. Among others, Lucie Delemotte was an invited speaker in the Membrane Biophysics Subgroup, describing her work On the selective promiscuity of calmodulin. Prior to the meeting, group members also found time for a quick hike through glorious Muir Woods National Monument.