Biophysics Colab

An innovative community-run journal based on the principles of open science

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Ribbon representation of
haemoglobin (PDB:5NI1) showing
two bound haem groups by Angela Ballesteros

Research Articles

Lipids and Membranes, Transporters and Pumps

Macromolecular condensation is unlikely to buffer intracellular osmolality

Alan R. Kay & Zahra Aminzare

“Kay and Aminzare discuss a claim made in a prior publication that macromolecular condensation acts as a water buffering mechanism in cells to compensate for the effects of osmotic shock. The authors argue that, although such a buffer could temporarily maintain a transmembrane osmolality differential, this differential would drive water across the membrane to reach a steady-state in which osmolality within the cell equals osmolality outside the cell. Using the well-established pump-leak model for osmotic water transport, they further show that the timescale at which a water buffer could maintain a modest 10% osmolality differential across the membrane is at most one minute for a typical animal cell.”

Article published 4 August 2025

Curated Preprints

Channels and Pores

ATP-release pannexin channels are gated by lysophospholipids

Erik Henze, Russell N. Burkhardt … Toshimitsu Kawate

“Pannexin (Panx) channels are a family of poorly understood large-pore channels that mediate the release of substrates like ATP from cells, yet the physiological stimuli that activate these channels remain poorly understood. The preprint by Henze et al. describes an elegant approach wherein activity-guided fractionation of mouse liver led to the discovery that lysophospholipids (LPCs) activate Panx1 and Panx2 channels expressed in cells or reconstituted into liposomes. The authors provide evidence that LPC-mediated activation of Panx1 is involved in joint pain and that Panx1 channels are required for the established effects of LPC on inflammasome activation in monocytes, suggesting that Panx channels play a role in inflammatory pathways. Overall, this important study reports a previously unanticipated mechanism wherein LPCs directly activate Panx channels.”

Preprint curated 13 February 2025

Channels and Pores, Lipids and Membranes

Structural basis of closed groove scrambling by a TMEM16 protein

Zhang Feng, Omar E. Alvarenga & Alessio Accardi

“Feng and colleagues investigate the molecular basis of lipid scrambling in a fungal member of the TMEM16 family of Ca²⁺-dependent lipid scramblases. These proteins possess a groove in their 3D structure that has been implicated in lipid scrambling, which the authors investigate in the absence and presence of Ca²⁺ using a combination of cryo-EM structure determination, mutagenesis and functional assays. Their closed-groove structure reveals a continuous file of lipid molecules around the catalytic groove region, providing a structural basis for lipid interaction with the protein. Additionally, the authors capture three novel states of TMEM16, completing the picture of conformational transitions that this protein undergoes. Strikingly, the authors show that both structure and distribution of the protein’s conformations depend on lipid composition and nanodisc scaffold protein.”

Preprint curated 22 February 2024

Channels and Pores, Lipids and Membranes, Receptors

Structure of an open K_ATP channel reveals tandem PIP₂ binding sites mediating the Kir6.2 and SUR1 regulatory interface

Camden M. Driggers, Yi-Ying Kuo … Show-Ling Shyng

“Driggers et al. is an elegant study that reports the structure of an open KATP channel complex formed from the Q52R diabetes mutation of the pore-forming subunit Kir 6.2, the sulfonylurea receptor (SUR1), and long-chain phosphatidylinositol 4,5-bisphosphate (PIP2) – a key lipid that stabilizes the open state of the channel and regulates inhibition by intracellular ATP. The structure reveals one PIP2 site related to that seen in other Kir channels as well as a second unanticipated one where the lipid snuggles into the interface between Kir6.2 and a region of SUR1 previously implicated in promoting the open state of KATP. This important finding helps to explain how PIP2 exerts such a profound regulatory influence on KATP.”

Preprint curated 12 January 2024

Receptors

Activation mechanism of the human Smoothened receptor

Prateek D. Bansal. Soumajit Dutta & Diwakar Shukla

“Bansal et al. present an atomistic view of the transition cascade of the class F GPCR Smoothened (Smo). The extensive long-range molecular dynamics simulations together with stochastic modelling provide theoretical insight into Smo activation and how this is modulated by different ligands. The work identifies testable hypotheses for functional studies of Smo and other class F GPCRs. Future simulations of regions beyond the seven-transmembrane bundle, particularly the cysteine-rich domain, will afford a more complete understanding of receptor activation.”

Preprint curated 24 August 2023

Lipids and Membranes, Transporters and Pumps

Structures and membrane interactions of native serotonin transporter in complexes with psychostimulants

Dongxue Yang, Zhiyu Zhao … Eric Gouaux

“Yang et al. present valuable information about ligand interactions with the serotonin transporter SERT, innovatively purified from pig brain using Fab fragments. The approach of using natively expressed SERT is notable for its potential insight into binding of endogenous membrane components such as lipids. Data distinguishing binding of the psychostimulants methamphetamine and cocaine add to our knowledge of substrate and inhibitor interactions with SERT and allow direct comparison with the closely related dopamine transporter DAT. The authors carefully state the limitations of their findings, including the possibility that the monomeric transporter stable in detergent micelles might exist in a multimeric state in native membranes.”

Preprint curated 22 August 2023

Receptors

Dynamic allosteric networks drive adenosine A₁ receptor activation and G-protein coupling

Miguel A. Maria-Solano & Sun Choi

“Maria-Solano and Choi present the dynamics underlying allostery of the adenosine A1 receptor, providing valuable insights into the receptor’s activation pathway. The enhanced sampling molecular dynamics simulations of available structural data, followed by network analysis, reveal transient conformational states and communication between functional regions. The authors carefully state the limitations of their work, including the restricted convergence of the free energy landscape and missing water-mediated hydrogen bond coordination. Collectively, the findings provide a convincing framework to advance rational design strategies of specific modulators with desired modes of action.”

Preprint curated 16 June 2023

Channels and Pores

Activation-pathway transitions in human voltage-gated proton channels revealed by a non-canonical fluorescent amino acid

Esteban Suárez-Delgado, M. E. Orozco-Contreras … León D. Islas

“The preprint by Suarez-Delgado et al. explores the mechanisms by which the Hv1 voltage-activated proton channel is dependent upon transmembrane voltage and pH by incorporating the small fluorescent non-canonical amino acid Anap into the S4 helix and monitoring its fluorescence. Anap spectra suggest the fluorophore resides in an aqueous environment and moves relative to a quenching aromatic residue (F150) in the S2 helix upon depolarization. Two kinetically distinct components of fluorescence change support the presence of at least three conformational states in the activation pathway of Hv1. Measurements using different pH gradients suggest that S4 movement and channel opening are similarly affected by pH gradients. This is the first study to incorporate Anap into Hv1, and provide a rigorous and thorough characterization of how the fluorophore can be used to explore mechanisms of gating and regulation, paving the way for future studies. The work will be of interest to physiologists and biophysicists investigating membrane protein mechanisms using non-canonical fluorescent amino acids.”

Preprint curated 23 December 2022

Channels and Pores, Lipids and Membranes

Membrane curvature governs the distribution of Piezo1 in live cells

Shilong Yang, Xinwen Miao … Zheng Shi

“The preprint by Yang et al. asks how the shape of the membrane influences the localization of mechanosensitive Piezo channels. The authors use a creative approach involving methods that distort the plasma membrane by generating blebs and artificial filopodia. They convincingly show that curvature of the lipid environment influences Piezo1 localization, such that increased curvature causes channel depletion, and that application of the chemical modulator Yoda1 is sufficient to allow channels to enter filopodia. The study provides support for a provocative “flattening model” of Yoda1 action, and should inspire future studies by researchers interested in mechanosensitive channels and membrane curvature.”

Preprint curated 6 December 2022

Receptors

Chloride ions evoke taste sensations by binding to the extracellular ligand-binding domain of sweet/umami taste receptors

Nanako Atsumi, Keiko Yasumatsu … Atsuko Yamashita

“The preprint by Atsumi et al. describes how chloride binding to sweet- and umami-sensing proteins (T1R taste receptors) can evoke taste sensation. The authors use an elegant combination of structural, biophysical and electrophysiological approaches to locate a chloride binding site in the ligand-binding domain of medaka fish T1r2a/3 receptors. They convincingly show that low mM concentrations of chloride induce conformational changes and, using single fiber recordings, establish that mouse chorda tympani nerves are activated by chloride in a T1R-dependent manner. This suggests that chloride binding to sweet receptors could mediate the commonly reported sweet taste sensation following ingestion of low concentrations of table salt. The findings will be of broad relevance to those studying taste sensation and ligand recognition in GPCRs.”

Preprint curated 17 November 2022

Channels and Pores, Transporters and Pumps

Tuning aromatic contributions by site-specific encoding of fluorinated phenylalanine residues in bacterial and mammalian cells

Grace D. Galles, Daniel T. Infield … Christopher A. Ahern

“The preprint by Galles et al. reports the generation of pyrrolysine-based aminoacyl-tRNA synthetases capable of incorporating fluorinated phenylalanine non-canonical amino acids into proteins expressed in either bacteria or mammalian cells. For the most extensively characterized synthetases, fluorinated phenylalanine derivatives were successfully incorporated into GFP and two membrane proteins (CFTR and Nav1.5) at expression levels adequate for biochemical studies, suggesting that the approach could be combined with multiple different structural and biophysical techniques. The work provides a valuable tool that will enable the functional role of cation-pi interactions to be interrogated in both soluble and integral membrane proteins.”

Preprint curated 6 October 2022

Channels and Pores, Transporters and Pumps

Mechanism of CFTR correction by type I folding correctors

Karol Fiedorczuk & Jue Chen

“The preprint by Fiedorczuk and Chen presents structures of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel in complex with type I correctors, a class of drug currently used to treat cystic fibrosis by targeting CFTR folding and stability. The strength of the paper lies in the consistency of the structural data with maturation and binding assays, as well as with much of the existing literature. Overall, the work represents a rigorous investigation of the mechanism of these drugs, and will be of interest to those who study cystic fibrosis, protein folding, and drug design.”

Preprint curated 28 April 2022

Channels and Pores

Single-molecule imaging with cell-derived nanovesicles reveals early binding dynamics at a cyclic nucleotide-gated ion channel

Vishal R. Patel, Arturo M. Salinas … Marcel P. Goldschen-Ohm

“The preprint by Patel et al. describes the development of a single molecule approach for studying individual ligand binding events in membrane proteins within native lipid environments. The approach represents an elegant way to investigate the dynamics of ligand binding, and potential relationships with conformational changes, in molecules embedded within physiological membranes. The work makes an important contribution that will be of interest to scientists working on molecular mechanisms in ion channels and other membrane proteins.”

Preprint curated 8 September 2021