Review
Biochemistry & Molecular Biology
Gregorio Fernandez-Ballester, Asia Fernandez-Carvajal, Antonio Ferrer-Montiel
Summary: The thermoTRP family of ion channels, which includes multiple nonselective cation channels, are activated by physical and chemical stimuli, functioning as polymodal receptors. These channels undergo gating through changes in temperature, osmolarity, voltage, pH, pressure, and by chemical compounds that bind to the proteins. Recent advances in cryo-electron microscopy techniques have provided high-resolution structures of these channels in different states, shedding light on the underlying allosteric gating mechanisms. Understanding these mechanisms is important for the development of drug-based therapies for diseases involving dysfunctional thermoTRP channels, such as chronic pain.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Yuqi Qin, Daqi Yu, Dan Wu, Jiangqing Dong, William Thomas Li, Chang Ye, Kai Chit Cheung, Yingyi Zhang, Yun Xu, YongQiang Wang, Yun Stone Shi, Shangyu Dang
Summary: This study determines the cryo-EM structure of mouse TMEM63C and reveals its structural differences compared to other TMEM63 proteins. The coupling of TM0 and TM6 is shown to play important roles in channel activity. Additionally, it is discovered that TMEM63C exists primarily as a monomer, while TMEM63B can exist as a mixture of monomer and dimer, suggesting oligomerization as a regulatory mechanism.
NATURE COMMUNICATIONS
(2023)
Article
Neurosciences
Zijing Chen, Maggie Kerwin, Orlaith Keenan, Craig Montell
Summary: This study identified the structural requirements for TRP channel function in Drosophila photoreceptor cells, including the roles of the S4-S5 linker and the TRP domain, as well as the differential requirements for two highly conserved motifs in the TRP domain for activation and protein stability. Genetic complementation experiments revealed an intrasubunit interaction between the S4-S5 linker and the S5 segment in Drosophila photoreceptor cells, which contributes to channel activation.
JOURNAL OF NEUROSCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Leo C. T. Ng, Brandon J. Harris, Megan Larmore, My C. Ta, Thuy N. Vien, Valerie L. Tokars, Vladimir Yarov-Yarovoy, Paul G. DeCaen
Summary: In this study, computational prediction tools were used to model missing PKD2L1 structural motifs and evaluate over 150 mutations in the entire pore module. Results revealed an energetic landscape of the polycystin pore and identified critical structural regulators controlling the conductive and nonconductive states of the polycystin ion channel.
Article
Biophysics
Vyacheslav S. S. Korkosh, Denis B. B. Tikhonov
Summary: The gating mechanism of ASICs is still not clear despite atomic-scale structures being available. Activation is assumed to be triggered by the collapse of the acidic pocket and structural changes in the low-palm region. Protonation of certain residues in the acidic pocket can minimize repulsion in the collapsed conformation. Our study supports a proposal of a gating mechanism in the low-palm region involving residues E80 and E417 sharing a proton.
EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS
(2023)
Article
Infectious Diseases
Evgeny G. Chulkov, Emery Smith, Claudia M. Rohr, Nawal A. Yahya, Sang-Kyu Park, Louis Scampavia, Timothy P. Spicer, Jonathan S. Marchant
Summary: This study optimized a high-throughput screening method for Schistosoma mansoni TRPMPZQ activity, leading to the discovery of a novel activator of Sm.TRPMPZQ and numerous potential blockers. The new activator, though distinct from PZQ, was similar to a known chemical entity identified through phenotypic screening.
PLOS NEGLECTED TROPICAL DISEASES
(2021)
Article
Oncology
Haojie Zhang, Xiangsheng Zhang, Xiaohong Wang, Hongguang Sun, Changran Hou, Yue Yu, Song Wang, Fangxu Yin, Zhenlin Yang
Summary: This study identified a risky formula based on the expression of TRP channel-related genes that can predict prognosis, therapeutic effect, and tumor microenvironment status in patients with TNBC.
FRONTIERS IN ONCOLOGY
(2022)
Article
Multidisciplinary Sciences
Quan Tian, Peiyu Wang, Chang Xie, Peiyuan Pang, Youjing Zhang, Yue Gao, Zhijian Cao, Yingliang Wu, Wenxin Li, Michael X. Zhu, Dongdong Li, Jing Yao
Summary: This study identified a channel in scorpions and fruit flies that senses natural repellents, providing insights into the mechanisms of arthropods' perception of these repellents. This knowledge is important for designing effective insect control strategies and conserving biodiversity.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biology
Thi Hong Dung Nguyen, Satoru G. Itoh, Hisashi Okumura, Makoto Tominaga
Summary: The study identified specific regions within TRPV1 and TRPV3 that confer sensitivity to monoterpenes and validated these findings through molecular dynamics simulations. The involvement of these amino acids differs between different TRP channels, revealing insights into how different TRP channels respond to chemical or heat stimuli.
COMMUNICATIONS BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Frank Yeh, Andres Jara-Oseguera, Richard W. Aldrich
Summary: Temperature influences dynamics and state-equilibrium distributions in molecular processes, and animals have evolved sensory ion channels to detect temperature changes with remarkable sensitivity. The molecular mechanisms behind the temperature-sensitivity of these channels and the adaptations that make them heat- or cold-activated are not well understood. This study challenges the assumption that the heat capacity difference (ACp) is constant by investigating the consequences of a temperature-dependent ACp on ion channel equilibrium and proposes new possibilities for ion channel gating models.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Linus J. Conrad, Peter Proks, Stephen J. Tucker
Summary: This passage discusses a voltage-dependent gating process in the TREK-2 K+ channel, which can be modulated by small molecule agonists and high internal K+ concentrations. It is found that high ionic-strength can inhibit the channel conductance, while the activatory effect of BL1249 on channel open probability persists under these conditions. The influence of negatively charged activators like BL1249 on permeation is consistent with an electrostatic mechanism, suggesting complexity in their effect on channel gating.
Article
Multidisciplinary Sciences
Toby S. Turney, Vivian Li, Stephen G. Brohawn
Summary: Researchers use cryo-EM and electrophysiology to discover the gating mechanism of the TWIK1 channel in response to lowered pH. They find that conformational changes at the selectivity filter lead to the closure of the channel. This study provides mechanistic insights into the pH-gating of TWIK1 and sheds light on the diversity of gating mechanisms in K+ channels.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Philipp A. M. Schmidpeter, John T. Petroff, Leila Khajoueinejad, Aboubacar Wague, Cheryl Frankfater, Wayland W. L. Cheng, Crina M. Nimigean, Paul M. Riegelhaupt
Summary: Tandem pore (K2P) potassium channels are influenced by the composition of phospholipids in the bilayer, which can directly alter their gating. This study provides insight into the molecular details of lipid modulation in K2P channels, revealing two distinct pathways by which anionic lipids enhance channel activity. The findings contribute to a model that integrates lipid gating with the effects of other mechanosensitive K2P modulators.
NATURE COMMUNICATIONS
(2023)
Article
Plant Sciences
Lorenzo Alibardi, Marta Surbek, Leopold Eckhart
Summary: EPS8L1 is expressed in the terminally differentiated cells of human epidermis, and it has also been detected in the granular layer of mammalian epidermis as well as the inner root sheath of hair follicles. EPS8L1 may have a role in regulating the skin barrier.
Article
Biotechnology & Applied Microbiology
Jason C. Hyun, Jonathan M. Monk, Bernhard O. Palsson
Summary: With the growth of publicly available genome sequences, comparative pangenomics methods have provided valuable insights into genetic diversity across multiple species. The study found that pangenome openness is associated with species' phylogenetic placement, gene function and frequency relationships are conserved across species, core genomes have high sequence diversity and functional diversity, and certain protein domains are consistently mutation enriched across multiple species.
Article
Biophysics
Koushik Choudhury, Marina A. Kasimova, Sarah McComas, Rebecca J. Howard, Lucie Delemotte
Summary: This study used molecular modeling and simulations to test possible open-state models of NavMs channels from the bacterium Magnetococcus marinus, finding that the experimental structure was unable to conduct ions at the activation gate. By observing a spontaneous transition and comparing with other Nav channels, an alternative stable open-state model was built, showing consistent pore hydration, ion permeation, and drug binding with the functional open state.
BIOPHYSICAL JOURNAL
(2022)
Article
Biochemistry & Molecular Biology
Ravi Patel, Vincenzo Carnevale, Sudhir Kumar
Summary: Research has shown that negative selection between sites creates more invariant sites compared to site-specific preferences alone, with an increasing role over longer evolutionary periods. These findings highlight the mechanistic role of epistasis in site invariance and evolutionary rates.
MOLECULAR BIOLOGY AND EVOLUTION
(2022)
Article
Biology
Damon J. A. Frampton, Koushik Choudhury, Johan Nikesjo, Lucie Delemotte, Sara Liin
Summary: The study reveals that polyunsaturated fatty acids (PUFAs) can facilitate the activation of one subtype of potassium channels while inhibiting the activation of another subtype. The response to PUFAs is dependent on the charge of the fatty acids and shows subtype-specific effects.
Article
Biology
Deny Cabezas-Bratesco, Francisco A. Mcgee, Charlotte K. Colenso, Kattina Zavala, Daniele Granata, Vincenzo Carnevale, Juan C. Opazo, Sebastian E. Brauchi
Summary: Transient receptor potential (TRP) proteins are a diverse family of cation-selective channels, with detailed mechanisms of regulation still under debate. Through analysis, a highly conserved set of residues was discovered in TRP channels, positioned at equivalent locations in different subtypes, potentially influencing coupling strategies of various subgroups.
Article
Biochemistry & Molecular Biology
Siyuan Zhao, Vincenzo Carnevale, Matthew Gabrielle, Eleonora Gianti, Tibor Rohacs
Summary: TRPM3 is a heat-activated ion channel that depends on PI(4,5)P-2 for its activity. Mutating residues involved in PI(4,5)P-2 binding increases sensitivity to TRPM3 inhibition. Additionally, PI(4,5)P-2 is involved in the regulation of TRPM8 and the inhibition by G beta gamma. Disease-associated gain-of-function TRPM3 mutations do not increase sensitivity to PI(4,5)P-2.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemical Research Methods
Annie M. Westerlund, Akshay Sridhar, Leo Dahl, Alma Andersson, Anna-Yaroslava Bodnar, Lucie Delemotte
Summary: Calmodulin (CaM) is a calcium-sensing protein that regulates other proteins by binding them in a calcium-dependent manner. Trifluoperazine (TFP), an antipsychotic drug, inhibits the ability of CaM to bind and regulate other proteins. In this study, we used molecular dynamics simulations, Markov state modeling, and machine learning to understand how TFP binding to one domain of CaM prevents its association with other proteins. We found that TFP promotes the adoption of a conformation similar to the calcium-unbound form of CaM, affecting different structural and dynamic features depending on its binding orientation. Understanding TFP binding is a crucial step towards developing improved drugs that target CaM.
PLOS COMPUTATIONAL BIOLOGY
(2022)
Article
Chemistry, Physical
Ruiyu Wang, Yunqian Zou, Richard C. Remsing, Naomi O. Ross, Michael L. Klein, Vincenzo Carnevale, Eric Borguet
Summary: Understanding the microscopic driving force of water wetting is challenging and important for material design. This study investigates the relations between structure, dynamics and hydrogen bonds of interfacial water on alumina surfaces using molecular dynamics simulations and experiments. The findings reveal superhydrophilicity of both surfaces, with the (0001) surface being more hydrophilic. The molecular dynamics simulations eliminate surface contamination and provide insights into the microscopic origin of the macroscopic superhydrophilicity: strong water-to-aluminol hydrogen bonds.
JOURNAL OF COLLOID AND INTERFACE SCIENCE
(2022)
Article
Chemistry, Multidisciplinary
Shaohua Zhang, Wei Li, Jiabin Luan, Abhinav Srivastava, Vincenzo Carnevale, Michael L. Klein, Jiawei Sun, Danni Wang, Serena P. Teora, Sjoerd J. Rijpkema, Johannes D. Meeldijk, Daniela A. Wilson
Summary: Researchers report an adaptive non-covalent binding strategy for surface functionalization using a hydrophobic anchor to insert into a poly(ethylene glycol) (PEG) host. This strategy allows for spontaneous loading of hydrophilic charged and non-charged functional modules onto the PEG surface without the need for catalysts or binding groups. The reversible insertion of the hydrophobic anchor enables programmable surface functionalization, challenging the current understanding of PEG in hydrophilicity and potentially advancing nanomedicine, advanced materials, and nanotechnology.
Article
Physics, Multidisciplinary
Antonio Suma, Vincenzo Carnevale, Cristian Micheletti
Summary: Using theory and simulations, the authors studied DNA unzipping via nanopore translocation and found three dynamical regimes depending on the applied force. They showed that the normal regime can be modeled as a one-dimensional stochastic process and used the theory of stochastic processes to recover the free-energy landscape. This approach can be applied to other single-molecule systems with periodic potentials to obtain detailed free-energy landscapes from out-of-equilibrium trajectories.
PHYSICAL REVIEW LETTERS
(2023)
Article
Chemistry, Medicinal
Phu K. Tang, Prabir Khatua, Vincenzo Carnevale, Sharon M. Loverde
Summary: In this study, the initial stages of self-assembly of a model drug amphiphile in an aqueous solution were characterized through atomistic molecular dynamics simulations. It was found that aromatic stacking of the drug molecules drove the formation of a higher-density liquid droplet, which elongated and formed a higher-ordered supramolecular assembly through reorganization and additional aromatic stacking. The development of novel reaction coordinates tailored to this class of molecules was shown to be essential in capturing the degree of molecular order during assembly. This approach can be extended to study the supramolecular assembly pathway of other molecules containing aromatic compounds.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Physical
Mohsen Farshad, Mark J. DelloStritto, Antonio Sum, Vincenzo Carneval
Summary: In this study, we analyzed a methanol/hexane mixture to investigate the phase diagram and structural changes associated with demixing. We found that the topological properties of the H-bond network abruptly change as the system crosses the demixing line, which can be detected using spectral clustering. We further validated the effectiveness of spectral clustering analysis in detecting demixing transitions in a Lennard-Jones system without H-bonds.
JOURNAL OF PHYSICAL CHEMISTRY B
(2023)
Article
Biology
Darko Mitrovic, Sarah E. McComas, Claudia Alleva, Marta Bonaccorsi, David Drew, Lucie Delemotte
Summary: In this study, we predicted the structures of the entire sugar porter superfamily in each state of the transport cycle using coevolution analysis and comparative modeling, and identified the molecular determinants of the transport cycle. This research is of great significance for understanding the functional mechanism of transport proteins.
Article
Biology
Sarah E. McComas, Tom Reichenbach, Darko Mitrovic, Claudia Alleva, Marta Bonaccorsi, Lucie Delemotte, David Drew, Randy B. Stockbridge
Summary: Glucose transporters (GLUT) play a crucial role in maintaining blood glucose homeostasis in mammals. In humans, there are 14 different GLUT isoforms that transport glucose and other monosaccharides with varying preferences and kinetics. Recent research on the malarial transporter PfHT1 and the fructose transporter GLUT5 suggests that the extracellular gate consisting of the TM7b helix is responsible for substrate promiscuity in these proteins. The findings challenge the traditional view of substrate specificity in GLUT proteins and suggest that allosteric coupling between sugar binding and the extracellular gate enables fast sugar flux at physiological blood glucose concentrations.
Article
Chemistry, Medicinal
Phu K. Tang, Prabir Khatua, Vincenzo Carnevale, Sharon M. Loverde
Summary: The initial stages of self-assembly of a model drug amphiphile in an aqueous solution were characterized using atomistic molecular dynamics simulations. Two-dimensional metadynamics calculations were performed to understand the assembly space of the model drug amphiphile Tubustecan, TT1. Aromatic stacking of the hydrophobic anticancer drug, Camptothecin (CPT), was found to drive the formation of a higher-density liquid droplet, which elongates and forms a higher-ordered supramolecular assembly through reorganization and additional aromatic stacking of the drugs. Novel reaction coordinates tailored to this class of molecules were shown to be essential in capturing the underlying degree of molecular order during assembly. This approach can be further refined and extended to study the supramolecular assembly pathway of other molecules containing aromatic compounds.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Multidisciplinary
Shaohua Zhang, Abhinav Srivastava, Wei Li, Sjoerd J. Rijpkema, Vincenzo Carnevale, Michael L. Klein, Daniela A. Wilson
Summary: An adaptive surface that can detect and respond to environmental changes is crucial for smart functional materials. This study presents a pH-responsive anchoring system on the poly(ethylene glycol) (PEG) corona of polymer vesicles. By reversibly protonating the covalently linked pH-sensing group, the hydrophobic anchor pyrene can be inserted into the PEG corona. The pH-responsive region can be engineered from acidic to neutral and basic conditions depending on the sensor's pKa. The switchable electrostatic repulsion between the sensors contributes to the responsive anchoring behavior. These findings offer a new responsive binding chemistry for the development of smart nanomedicine and nanoreactors.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)