Explanipedia

Characterisation of an unusual nicotinic acetylcholine receptor subtype preferentially sensitive to biogenic amines Open

Eleanor L. Mitchell, Emily B. Armstrong, Franco Viscarra, Isabel Bermúdez, Philip C. Biggin , et al. · 2025

Nicotinic acetylcholine receptors (nAChRs) are best known for mediating the fast actions of acetylcholine. However, the spectrum of other neurotransmitters possibly acting on these receptors is not well understood. Here, we report that the…

Can AI-Predicted Complexes Teach Machine Learning to Compute Drug Binding Affinity? Open

Wei-Tse Hsu, Savva Grevtsev, Anna M. Herz, Thomas Douglas, Aniket Magarkar , et al. · 2025

We evaluate the feasibility of using co-folding models for synthetic data augmentation in training machine learning-based scoring functions (MLSFs) for binding affinity prediction. Our results show that performance gains depend critically …

Asymmetric gating of a homopentameric ion channel GLIC revealed by cryo-EM Open

Zhuowen Li, Nikhil Bharambe, Kashmiri Manishrao Lande, Bjarne Feddersen, Asha Manikkoth Balakrishna , et al. · 2025

Pentameric ligand-gated ion channels (pLGICs) are vital neurotransmitter receptors that are key therapeutic targets for neurological disorders. Although the high-resolution structures of these channels have been elucidated, capturing their…

Structural basis for pH-responsive amino acid transport via SLC7A4 Open

Simon Newstead, Dimitrios Kolokouris, Asim Bothra, T. Kato, Yi C. Zeng , et al. · 2025

The transport of amino acids across cell membranes is essential for metabolism, neuronal signalling, and immune system function. The amino acid polyamine organocation (APC) superfamily regulates amino acid transport through various mechani…

Structural determinants for GqPCR-mediated inhibition of TASK K2P K<sup>+</sup> channels and their dysfunction in disease Open

Thibault Jouen-Tachoire, Peter Proks, David Seiferth, Kate M. Crowther, Philip C. Biggin , et al. · 2025

Two-Pore Domain K + (K2P) channels are crucial determinants of cellular electrical excitability. TASK-1 and TASK-3 K2P channels regulate the resting membrane potential in many different cell types where their activity is also coupled to Gq…

Steric control of signaling bias in the immunometabolic receptor GPR84 Open

Pinqi Wang, Xuan Zhang, A. -K. Guseinov, Laura Jenkins, Carl von Hallerstein , et al. · 2025

Biased signaling in G protein-coupled receptors offers therapeutic promise, yet rational design of biased ligands remains challenging due to limited mechanistic understanding. Here, we report a molecular framework for controlling signaling…

Can AI-predicted complexes teach machine learning to compute drug binding affinity? Open

Wei-Tse Hsu, Savva Grevtsev, Thomas Douglas, Aniket Magarkar, Philip C. Biggin · 2025

We evaluate the feasibility of using co-folding models for synthetic data augmentation in training machine learning-based scoring functions (MLSFs) for binding affinity prediction. Our results show that performance gains depend critically …

Structure-Activity-Relationships can be directly extracted from high-throughput crystallographic evaluation of fragment elaborations in crude reaction mixtures Open

Harold Grosjean, Kate K. Fieseler, Rubén Sánchez-García, Warren Thompson, Charlotte M. Deane , et al. · 2025

Fragment hits serve as starting points for lead-like compound development. A common approach to advancing from fragments is to build structure-activity relationships (SARs) from close analogues. One strategy involves performing automated c…

Allosteric Control of Super-Agonism in a Ligand-Gated Ion Channel Open

Franco Viscarra, Teresa Minguez, Isabel Bermúdez, Philip C. Biggin · 2025

Ligand-gated ion channels open in response to the binding of an agonist. The agonist binding site is typically located tens of Angstroms away from the channel gate, which lies within the membrane and thus the gating mechanism is considered…

Advanced computational methods in protein simulations — A case study of enhanced sampling applied to membrane transporters Open

Jonathan D. Colburn, Simon M Lichtinger, Philip C. Biggin · 2025

We review the use of state-of-the-art enhanced sampling techniques in molecular dynamics (MD) simu- lations. We briefly introduce the principles and practical considerations underlying the application of these methods, making reference to …

The need to implement FAIR principles in biomolecular simulations Open

Rommie E. Amaro, Johan Åqvist, İvet Bahar, Federica Battistini, Adam Bellaiche , et al. · 2025

International audience

Binding‐Site Purification of Actives (B‐SPA) Enables Efficient Large‐Scale Progression of Fragment Hits by Combining Multi‐Step Array Synthesis With HT Crystallography Open

Harold Grosjean, Anthony Aimon, Storm Hassell‐Hart, Warren Thompson, L. Koekemoer , et al. · 2025

Fragment approaches are long‐established in target‐based ligand discovery, yet their full transformative potential lies dormant because progressing the initial weakly binding hits to potency remains a formidable challenge. The only credibl…

Binding‐Site Purification of Actives (B‐SPA) Enables Efficient Large‐Scale Progression of Fragment Hits by Combining Multi‐Step Array Synthesis With HT Crystallography Open

Harold Grosjean, Anthony Aimon, Storm Hassell‐Hart, Warren Thompson, L. Koekemoer , et al. · 2025

Fragment approaches are long‐established in target‐based ligand discovery, yet their full transformative potential lies dormant because progressing the initial weakly binding hits to potency remains a formidable challenge. The only credibl…

Narrowing the gap between machine learning scoring functions and free energy perturbation using augmented data Open

ísak Valsson, Matthew T. Warren, Charlotte M. Deane, Aniket Magarkar, Garrett M. Morris , et al. · 2025

GLIC Y251A mutant in MSP1E3D1 nanodisc at pH 2.5 Open

Bjarne Feddersen, Asha Manikkoth Balakrishna, Philip C. Biggin, Sandip Basak · 2025

GLIC in MSP1E3D1 nanodisc at pH 7.5 (asolectin) Open

Nikhil Bharambe, David Seiferth, Asha Manikkoth Balakrishna, Philip C. Biggin · 2025

Mechanisms underlying modulation of human GlyRα3 by Zn <sup>2+</sup> and pH Open

Kayla Kindig, Eric Gibbs, David Seiferth, Philip C. Biggin, Sudha Chakrapani · 2024

Glycine receptors (GlyRs) regulate motor control and pain processing in the central nervous system through inhibitory synaptic signaling. The subtype GlyRα3 expressed in nociceptive sensory neurons of the spinal dorsal horn is a key regula…

GLIC in MSP1E3D1 nanodisc at pH 5.5 Open

Nikhil Bharambe, Zhuowen Li, David Seiferth, Asha Manikkoth Balakrishna, Philip C. Biggin , et al. · 2024

Analysis of Glycan Recognition by Concanavalin A Using Absolute Binding Free Energy Calculations Open

Sondos Musleh, Irfan Alibay, Philip C. Biggin, Richard A. Bryce · 2024

Carbohydrates are key biological mediators of molecular recognition and signaling processes. In this case study, we explore the ability of absolute binding free energy (ABFE) calculations to predict the affinities of a set of five related …

Structural basis for antibiotic transport and inhibition in PepT2 Open

Joanne L. Parker, Justin C. Deme, Simon M Lichtinger, Gabriel Kuteyi, Philip C. Biggin , et al. · 2024

Challenges of Absolute Binding Free Energies for Membrane Exposed Binding Pockets Open

Charlie Cook, Irfan Alibay, Nithishwer Anand Mouroug, Ewa I. Chudyk, Ron Knegtel , et al. · 2024

Absolute binding free energy (ABFE) calculations are finding increasing use within drug discovery programs, particularly as they can be performed on very different ligand scaffolds and direct comparisons made between them. They also have t…

Plasticity of the selectivity filter is essential for permeation in lysosomal TPC2 channels Open

A. Zaki, Süleyman Selim Çınaroğlu, Taufiq Rahman, Sandip Patel, Philip C. Biggin · 2024

Two-pore channels are pathophysiologically important Na + - and Ca 2+ -permeable channels expressed in lysosomes and other acidic organelles. Unlike most other ion channels, their permeability is malleable and ligand-tuned such that when g…

The need to implement FAIR principles in biomolecular simulations Open

Rommie E. Amaro, Johan Åqvist, İvet Bahar, Federica Battistini, Adam Bellaiche , et al. · 2024

This letter illustrates the opinion of the molecular dynamics (MD) community on the need to adopt a new FAIR paradigm for the use of molecular simulations. It highlights the necessity of a collaborative effort to create, establish, and sus…

The mechanism of mammalian proton-coupled peptide transporters Open

Simon M Lichtinger, Joanne L. Parker, Simon Newstead, Philip C. Biggin · 2024

Proton-coupled oligopeptide transporters (POTs) are of great pharmaceutical interest owing to their promiscuous substrate binding site that has been linked to improved oral bioavailability of several classes of drugs. Members of the POT fa…

Author response: The mechanism of mammalian proton-coupled peptide transporters Open

Simon M Lichtinger, Joanne L. Parker, Simon Newstead, Philip C. Biggin · 2024

Exploring the influence of pore shape on conductance and permeation Open

David Seiferth, Philip C. Biggin · 2024

There are increasing numbers of ion channel structures featuring heteromeric subunit assembly, exemplified by synaptic α1β_B glycine and α4β2 nicotinic receptors. These structures exhibit inherent pore asymmetry, but the relevanc…

Analysis of protein-glycan recognition using absolute binding free energies Open

Richard A. Bryce, Irfan Alibay, Philip C. Biggin, Sondos Musleh · 2024

Carbohydrates are key biological mediators of molecular recognition and signalling processes. In this work, we explore the ability of absolute binding free energy (ABFE) calculations to predict the affinities of a set of five related carbo…

How to make machine learning scoring functions competitive with FEP Open

Matthew T. Warren, ísak Valsson, Charlotte M. Deane, Aniket Magarkar, Garrett M. Morris , et al. · 2024

Machine learning offers a promising approach for fast and accurate binding affin- ity predictions. However, current models often fail to generalise beyond their training data and are not robustly evaluated on a diverse range of benchmarks,…

Author response: The mechanism of mammalian proton-coupled peptide transporters Open

Simon M Lichtinger, Joanne L. Parker, Simon Newstead, Philip C. Biggin · 2024

Proton-coupled oligopeptide transporters (POTs) are of great pharmaceutical interest owing to their promiscuous substrate binding site that has been linked to improved oral bioavailability of several classes of drugs. Members of the POT fa…

Reviewer #1 (Public Review): The mechanism of mammalian proton-coupled peptide transporters Open

Simon M Lichtinger, Joanne L. Parker, Simon Newstead, Philip C. Biggin · 2024

Proton-coupled oligopeptide transporters (POTs) are of great pharmaceutical interest owing to their promiscuous substrate binding site that has been linked to improved oral bioavailability of several classes of drugs. Members of the POT fa…

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