News

Publications

Otop Proton Paths

From the June 2019 issue of Nature Structural & Molecular Biology (v. 26 pp. 528–530):

Outlining the proton-conduction pathway in otopetrin channels

Lucie Delemotte

New structural work sheds light on the architecture of otopetrin channels, offering insights into the mechanisms for proton permeation in this family.

Read the full News & Views article here, referencing the publication Structures of the otopetrin proton channels Otop1 and Otop3 by Saotome & colleagues.

News

Channels on the Coast

Four current and former members of Molecular Biophysics Stockholm, along with multiple collaborators, presented their research at the 2019 Jacques Monod Conference Canaux ioniques activés par les ligands: de la structure atomique à la transmission synaptique (Ligand-gated ion channels from atomic structure to synaptic transmission) 24–29 May 2019 in Roscoff, France. Among others, Reba Howard gave an invited talk on Biochemical and simulation studies of allosteric mechanisms in a model Cys-loop receptor.

News

Biophysics Abroad

Molecular Biophysics Stockholm again hosted two US undergraduates through the DIS-Study Abroad in Scandinavia Stockholm program in Spring 2019. Under the supervision of Reba Howard and Urška Rovšnik, Sarah Komon (Wheaton College) and Nicole Sanford (St Olaf College) worked ≥20 hours per week on independent projects in the Ligand-Gated Ion Channels team throughout the term, including data collection at both the Science for Life Laboratory and Umeå University. Each presented a research poster at the DIS End-of-Semester Symposium, 7 May 2019 at Stockholm’s Kungliga Musikhögskolan. For an interview with Komon and Sanford regarding their experiences, visit the DIS blog Discover Study Abroad.

Two new DIS students will initiate research projects with the team in Fall 2019. For more information, contact Reba or DIS-Stockholm.

News

Group Retreat 2019

Thirty members of Molecular Biophysics Stockholm, representing thirteen countries and a range of research areas, gathered for our annual spring retreat on 8 April 2019 at the Science for Life Laboratory in Solna, Sweden. Gabriella Fägerlind of Uppsala’s Implement Diversity AB led a workshop on inclusivity and psychological safety in the academic workplace, followed by small- and large-group exercises around goal-setting and group resource development, and an evening pizza party.

Publications

eBDIMS Server

Accepted manuscript, Bioinformatics 2019. Posted online ahead of print 19 February 2019

eBDIMS server: protein transition pathways with ensemble analysis in 2D-motion spaces

Laura Orellana, Johan Gustavsson, Cathrine Bergh, Ozge Yoluk, Erik Lindahl

Understanding how proteins transition between different conformers, and how conformers relate to each other in terms of structure and function, is not trivial. Here, we present an online tool for transition pathway generation between two protein conformations using Elastic Network Driven Brownian Dynamics Importance Sampling, a coarse-grained simulation algorithm, which spontaneously predicts transition intermediates trapped experimentally. In addition to path-generation, the server provides an interactive 2D-motion landscape graphical representation of the transitions or any additional conformers to explore their structural relationships.

Read the full publication here.

Publications

How to create open access and reproducible molecular simulations

From January 10, 2019 release of PLOS Computational Biology (v. 15 pp. 1-4)

Ten simple rules on how to create open access and reproducible molecular simulations of biological systems

Arne Elofsson, Berk Hess, Erik Lindahl, Alexey Onufriev, David van der Spoel, Anders Wallqvist

All PLOS journals have an open data policy that, amongst other things, states that all data and related metadata underlying the findings reported in a submitted manuscript should be deposited in an appropriate public repository, or for smaller datasets, as supporting information. This should obviously apply to computational methods as well, but unfortunately this is not always applied in practice, although it is of greatest importance for the scientific quality of simulations and other modeling projects.

Molecular dynamics and other type of simulations have become a fundamental part of life sciences. The simulations are dependent on a number of parameters such as force fields, initial configurations, simulation protocols, and software. Researchers have different opinions about the types of software they prefer, and in general, we believe authors should be free to choose the tools that best fit their needs. However, as scientists, we also have a common obligation to critically test each other’s statements to find mistakes (including errors in the algorithms and bugs in the code), which can be exemplified by a heated debate over simulations of supercooled water that ended up being due to a subtle algorithmic issue, and we believe PLOS has a particularly strong responsibility to lead this development even if it might cause some short-term grief.

In particular, all published results should, in principle, be possible to reproduce independently by scientists in other labs using different tools. To ensure this, we propose a set of standards that any publication in PLOS Computational Biology, and hopefully, publications in other journals as well, should follow. We do believe that the sooner such policies are widely adapted, the more open and collaborative science will flourish.

These 10 simple rules should not be limited to molecular dynamics but also include Monte Carlo simulations, quantum mechanics calculations, molecular docking, and any other computational methods involving computations on biological molecules.

Read the full publication here.

Publications

e-Science in Scandinavia

From the December 2018 release of Informatik Spektrum (v. 41 pp. 398–404):

e-Science in Scandinavia: The Case of the Swedish e-Science Research Center

Olivia Eriksson, Erwin Laure, Erik Lindahl, Dan Henningson & Anders Ynnerman

The Swedish e-Science Research Centre (SeRC) is based on a collaboration between four Swedish universities: The KTH Royal Institute of Technology (KTH), Stockholm University (SU), Karolinska Institutet (KI) and Linköping University (LiU). SeRC’s mission statement is to develop state-of-the-art eScience tools and provide e-infrastructure support to existing and emerging e-Science research communities to help bring about scientific breakthroughs in Sweden. SeRC was founded in 2010 as the result of the Strategic Research Area (SRA) initiative launched by the Swedish Government Bill on Research Policy in 2008, where a total of 24 different strategic research areas were defined – one of which was e-Science. Initially SeRC was granted funding for 5 years. During those first 5 years, SeRC built up an organization for e-Science research, which has been highly successful. This was reflected in the excellent grades that SeRC received when the SRAs in Sweden were evaluated in 2015, and the fact that after this, SeRC received funding for at least 5 more years. This new phase of SeRC partly focuses on activities relating to emerging technologies (such as exascale systems and data-driven science) while also consolidating SeRC’s ongoing efforts in working towards a long-lasting e-Science environment in Sweden.

Read the full publication here.

News

Workshopping Sharing

Eight members of Molecular Biophysics Stockholm helped host an international workshop on Sharing Data from Molecular Simulations, 25–27 November on Lidingö in the Stockholm archipelago. Researchers from 13 institutions in 8 countries sought to explore and improve the dissemination of data and code related to molecular simulations and related methods in computational biology/chemistry. Major topics included:

  • Standardization of file formats
  • Tools for trajectory sharing
  • Streamlining molecular simulations data
  • Reproducibility of molecular simulations

Lucie Delemotte and Reba Howard co-organized the workshop with Matthieu Chavent (IPBS), Daniel Smith (MolSSI), and Mikael Trellet (Utrecht), with sponsorship from Rossen Apostolov at BioExcel. Among the participants were session chair Mark Abraham and invited speaker Erik Lindahl.

Although this exploratory workshop was limited in scale, organizers sought to maximize transparency by live-tweeting the proceedings (#SDMS18) and making videos of all talks and roundtable discussions, as well as original presentation slides, available for download via BioExcel.

A follow-up event, organized by MolSSI, is planned for 2019 in the USA.

News

Biophysics Abroad

Molecular Biophysics Stockholm was the first external research site to host US undergraduates through the recently launched DIS-Study Abroad in Scandinavia Stockholm program in Fall 2018. Under the supervision of Reba Howard, Isabel Anaya (Northwestern University) and Jaewon Kang (Vassar College) worked ≥20 hours per week on independent research projects in the Ligand-Gated Ion Channels team throughout the term. Both presented posters on their work at the DIS End-of-Semester Symposium, 11 December 2018 at Stockholm’s Kungliga Musikhögskolan.

Two new DIS students will initiate research projects with the team in Spring 2019. For more information, contact Reba or DIS-Stockholm.

Publications

RELION Refined

Accepted manuscript, posted ahead of online November 9, 2018 in eLife (v. 7 art. e42166):

New tools for automated high-resolution cryo-EM structure determination in RELION-3

Jasenko Zivanov, Takanori Nakane, Björn O Forsberg, Dari Kimanius, Wim JH Hagen, Erik Lindahl & Sjors HW Scheres

Here, we describe the third major release of RELION. CPU-based vector acceleration has been added in addition to GPU support, which provides flexibility in use of resources and avoids memory limitations. Reference-free autopicking with Laplacian-of-Gaussian filtering and execution of jobs from python allows non-interactive processing during acquisition, including 2D-classification, de novo model generation and 3D-classification. Per-particle refinement of CTF parameters and correction of estimated beam tilt provides higher-resolution reconstructions when particles are at different heights in the ice, and/or coma-free alignment has not been optimal. Ewald sphere curvature correction improves resolution for large particles. We illustrate these developments with publicly available data sets: together with a Bayesian approach to beam-induced motion correction it leads to resolution improvements of 0.2–0.7 Å compared to previous RELION versions.

Read the full publication here.

News

Multiscale Modeling in Tokyo

Five members of Molecular Biophysics Stockholm presented their research and discussed prospective collaborations at the 2nd Stockholm-Tokyo University Partnership Workshop, held this year in Japan, 28–30 October 2018. Among others, Erik Lindahl co-chaired a plenary session on Biological Mechanisms Regulating Healthy and Maladaptive Aging, and co-coordinated a satellite workshop on New Technologies: Multiscale Computation. Following the workshop, group members were generously hosted by their University of Tokyo colleagues in multiscale simulations and electron microscopy for a traditional meal in the Hongō district.

News

Grattis till Docent Delemotte

Members of Molecular Biophysics Stockholm celebrated Lucie Delemotte’s Swedish-language Docent Lecture in Applied Physics at KTH Royal Institute of Technology, Structural dynamics of voltage-gated ion channels and implications for health and disease, 24 October 2018 at AlbaNova Universitetscentrum in Stockholm, Sweden. With new funding recently awarded by Vetenskapsrådet, the Delemotte team stands poised grow in size and contribution. Check back soon for new openings!

MPIBPC
News

GROMACS Workshop October 2018

The 2018 workshop, 17–19 October in Göttingen, set out to 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 included:

  • 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?

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.

Publications

Dynamic Basis for Drug Binding

From the October 16, 2018 issue of Proceedings of the National Academy of Sciences of the USA (v. 115 pp. 10672–10677):

Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity

Stephanie A Heusser, Marie Lycksell, Xueqing Wang, Sarah E McComas, Rebecca J Howard & Erik Lindahl

Molecular mechanisms of general anesthetic modulation in pentameric ligand-gated ion channels remain controversial. Here we present molecular simulations and functional data that reveal correlations between dynamic differences in a membrane-accessible cavity and dramatic anesthetic effects, separate inhibitory and potentiating effects within the same electrophysiology recordings, and support a model for communication between the lipid bilayer and ion channel pore. In particular, enhanced electrostatic interactions in the membrane-accessible site were associated with a unique mode of anesthetic potentiation, persisting tens of minutes after washout. These results offer a bridge between lipid- and receptor-based theories of anesthesia, with the potential to inform both mechanistic understanding and drug development.

Read the full publication here.

News

Grattis till Licentiate Westerlund

Members of Molecular Biophysics Stockholm celebrated Annie Westerlund’s successful defense of her Licentiate thesis in Biophysics from KTH Royal Institute of Technology, Computational Study of Calmodulin’s Ca2+-dependent Conformational Ensembles, 3 October 2018 at the Science for Life Laboratory in Solna, Sweden. Professor Björn Wallner (Linköping University) served as opponent, and Professors Lucie Delemotte (KTH) and Erik Lindahl (KTH & Stockholm University) led a toast to their advisee of two years.

Publications

Sweet Simulations

From the September 25, 2018 issue of Scientific Reports (v. 8 art. 14324):

Uptake dynamics in the Lactose permease (LacY) membrane protein transporter

Dari Kimanius, Erik Lindahl & Magnus Andersson

The sugar transporter Lactose permease (LacY) of Escherichia coli has become a prototype to understand the underlying molecular details of membrane transport. Crystal structures have trapped the protein in sugar-bound states facing the periplasm, but with narrow openings unable to accommodate sugar. Therefore, the molecular details of sugar uptake remain elusive. In this work, we have used extended simulations and metadynamics sampling to explore a putative sugar-uptake pathway and associated free energy landscape. We found an entrance at helix-pair 2 and 11, which involved lipid head groups and residues Gln 241 and Gln 359. Furthermore, the protein displayed high flexibility on the periplasmic side of Phe 27, which is located at the narrowest section of the pathway. Interactions to Phe 27 enabled passage into the binding site, which was associated with a 24 ± 4 kJ/mol binding free energy in excellent agreement with an independent binding free energy calculation and experimental data. Two free energy minima corresponding to the two possible binding poses of the lactose analog β-D-galactopyranosyl-1-thio-β-D-galactopyranoside (TDG) were aligned with the crystal structure-binding pocket. This work outlines the chemical environment of a putative periplasmic sugar pathway and paves way for understanding substrate affinity and specificity in LacY.

Corresponding author and former group member Magnus Andersson can now be reached at Umeå University. Read the full publication here.

Publications

Commentary: Opening Leads to Closing

Commentary for the October 1, 2018 issue of the Journal of General Physiology (v. 150 art. 1356):

Opening leads to closing: Allosteric crosstalk between the activation and inactivation gates in KcsA

Lucie Delemotte

Voltage-gated potassium (Kv) channels control a number of different physiological processes, including the firing rate in axons. Such K+ channels display a reduction of conductance after exposure to a prolonged activating stimulus. This process, referred to as inactivation, causes repolarization of the cell membrane after the depolarizing phase of an action potential. The transient openings that result from it also allow neurons to readily fire a new action potential. Two types of inactivation mechanisms have been described in Kv channels (Hoshi et al., 1990). Fast inactivation, also called N-type inactivation, results from a mechanism that has been ascribed to pore blocking by a N-terminal peptide. Slow inactivation, or C-type inactivation, is revealed upon suppression of fast inactivation and is thought to be due to a conformational change occurring within the pore of the channel. While the structural basis of C-type inactivation appears to have been established, how it is dynamically coupled to channel activation remains to be understood in detail. In the Journal of General Physiology, a new study (see Li et al. 2018) proposes an intriguing mechanism for the allosteric control of C-type inactivation by the activation gate in the bacterial K+ channel KcsA.

Read the full commentary here.

Publications

Who Dances With an Electric Beat?

For the October 1, 2018 issue of the Journal of General Physiology (v. 150 art. 1444):

Determining the molecular basis of voltage sensitivity in membrane proteins

Marina A. Kasimova, Erik Lindahl & Lucie Delemotte

Voltage-sensitive membrane proteins are united by their ability to transform changes in membrane potential into mechanical work. They are responsible for a spectrum of physiological processes in living organisms, including electrical signaling and cell-cycle progression. Although the mechanism of voltage-sensing has been well characterized for some membrane proteins, including voltage-gated ion channels, even the location of the voltage-sensing elements remains unknown for others. Moreover, the detection of these elements by using experimental techniques is challenging because of the diversity of membrane proteins. Here, we provide a computational approach to predict voltage-sensing elements in any membrane protein, independent of its structure or function. It relies on an estimation of the propensity of a protein to respond to changes in membrane potential. We first show that this property correlates well with voltage sensitivity by applying our approach to a set of voltage-sensitive and voltage-insensitive membrane proteins. We further show that it correctly identifies authentic voltage-sensitive residues in the voltage-sensor domain of voltage-gated ion channels. Finally, we investigate six membrane proteins for which the voltage-sensing elements have not yet been characterized and identify residues and ions that might be involved in the response to voltage. The suggested approach is fast and simple and enables a characterization of voltage sensitivity that goes beyond mere identification of charges. We anticipate that its application before mutagenesis experiments will significantly reduce the number of potential voltage-sensitive elements to be tested.

Read the commentary in the same issue by Caitlin Sedwick, or see the paper here!

Publications

Human Skin Barrier Structure

Featured on the August 2018 cover of Journal of Structural Biology (v. 203 pp. 149–161):

Human skin barrier structure and function analyzed by cryo-EM and molecular dynamics simulation

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

In the present study we have analyzed the molecular structure and function of the human skin’s permeability barrier using molecular dynamics simulation validated against cryo-electron microscopy data from near native skin.

The skin’s barrier capacity is located to an intercellular lipid structure embedding the cells of the superficial most layer of skin – the stratum corneum. According to the splayed bilayer model (Iwai et al., 2012) the lipid structure is organized as stacked bilayers of ceramides in a splayed chain conformation with cholesterol associated with the ceramide sphingoid moiety and free fatty acids associated with the ceramide fatty acid moiety. However, knowledge about the lipid structure’s detailed molecular organization, and the roles of its different lipid constituents, remains circumstantial.

Starting from a molecular dynamics model based on the splayed bilayer model, we have, by stepwise structural and compositional modifications, arrived at a thermodynamically stable molecular dynamics model expressing simulated electron microscopy patterns matching original cryo-electron microscopy patterns from skin extremely closely. Strikingly, the closer the individual molecular dynamics models’ lipid composition was to that reported in human stratum corneum, the better was the match between the models’ simulated electron microscopy patterns and the original cryo-electron microscopy patterns. Moreover, the closest-matching model’s calculated water permeability and thermotropic behaviour were found compatible with that of human skin.

The new model may facilitate more advanced physics-based skin permeability predictions of drugs and toxicants. The proposed procedure for molecular dynamics based analysis of cellular cryo-electron microscopy data might be applied to other biomolecular systems.

Read the full publication here.

Publications

Boosting Efficiency With Riemann Metrics

From the August 30, 2018 issue of Physical Review E (v. 98 art. 023312):

Riemann metric approach to optimal sampling of multidimensional free-energy landscapes

Viveca Lindahl, Jack Lidmar & Berk Hess

Exploring the free-energy landscape along reaction coordinates or system parameters λ is central to many studies of high-dimensional model systems in physics, e.g., large molecules or spin glasses. In simulations this usually requires sampling conformational transitions or phase transitions, but efficient sampling is often difficult to attain due to the roughness of the energy landscape. For Boltzmann distributions, crossing rates decrease exponentially with free-energy barrier heights. Thus, exponential acceleration can be achieved in simulations by applying an artificial bias along λ tuned such that a flat target distribution is obtained. A flat distribution is, however, an ambiguous concept unless a proper metric is used and is generally suboptimal. Here we propose a multidimensional Riemann metric, which takes the local diffusion into account, and redefine uniform sampling such that it is invariant under nonlinear coordinate transformations. We use the metric in combination with the accelerated weight histogram method, a free-energy calculation and sampling method, to adaptively optimize sampling toward the target distribution prescribed by the metric. We demonstrate that for complex problems, such as molecular dynamics simulations of DNA base-pair opening, sampling uniformly according to the metric, which can be calculated without significant computational overhead, improves sampling efficiency by 50%–70%.

Read the full publication here.

Publications

Predicting Permeability through Skin

From the August 10, 2018 release of Journal of Controlled Release (v. 283 pp. 269–279):

Predicting drug permeability through skin using molecular dynamics simulation

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

Understanding and predicting permeability of compounds through skin is of interest for transdermal delivery of drugs and for toxicity predictions of chemicals. We show, using a new atomistic molecular dynamics model of the skin’s barrier structure, itself validated against near-native cryo-electron microscopy data from human skin, that skin permeability to the reference compounds benzene, DMSO (dimethyl sulfoxide), ethanol, codeine, naproxen, nicotine, testosterone and water can be predicted. The permeability results were validated against skin permeability data in the literature. We have investigated the relation between skin barrier molecular organization and permeability using atomistic molecular dynamics simulation. Furthermore, it is shown that the calculated mechanism of action differs between the five skin penetration enhancers Azone, DMSO, oleic acid, stearic acid and water. The permeability enhancing effect of a given penetration enhancer depends on the permeating compound and on the concentration of penetration enhancer inside the skin’s barrier structure. The presented method may open the door for computer based screening of the permeation of drugs and toxic compounds through skin.

Read the full publication here.

Publications

Contact Line Friction in Dynamic Wetting

From the July 2018 release of Physical Review Fluids (v. 3 art. 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.

Publications

Frozen in Motion

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

Characterisation of molecular motions in cryo-EM single-particle data by multi-body refinement in RELION

Takanori Nakane, Dari Kimanius, Erik Lindahl & Sjors HW 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.