Article
Biochemistry & Molecular Biology
Michelle Redhair, William M. Atkins
Summary: The article discusses the importance of ligand-dependent changes in protein conformation in biology, introducing the induced fit and conformational selection mechanisms, and explaining their impact on protein substrate specificity, promiscuity, and regulatory properties. It also presents a new perspective based on interactions between protein ensembles and ligand ensembles, and describes how probing protein ensembles with multiple ligands can optimize mechanistic information.
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2021)
Article
Biochemistry & Molecular Biology
Monica L. Fernandez-Quintero, Clarissa A. Seidler, Patrick K. Quoika, Klaus R. Liedl
Summary: Sharks and other cartilaginous fish are phylogenetically oldest living organisms with antibodies as part of their adaptive immune system. The research on V-NAR antibodies reveals a substantial rigidification upon affinity maturation, leading to a decrease in flexibility and an increase in stabilizing interactions. Additionally, the V-NAR antibodies follow the concept of conformational selection, with a strong population shift towards the native binding pose upon affinity maturation.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Multidisciplinary Sciences
Tushar Modi, Valeria A. Risso, Sergio Martinez-Rodriguez, Jose A. Gavira, Mubark D. Mebrat, Wade D. Van Horn, Jose M. Sanchez-Ruiz, S. Banu Ozkan
Summary: TEM-1 β-lactamase evolved from ancestral enzymes that degraded a variety of β-lactam antibiotics with moderate efficiency and degrades β-lactam antibiotics with a strong preference for penicillins. The authors developed a computational approach to rationally mold a protein flexibility profile based on a hinge-shift mechanism and successfully engineered a putative Precambrian β-lactamase that mimics the modern TEM-1 β-lactamase with only 21 amino acid replacements.
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
H. J. Kim, Y. Xu, A. Petri, K. Vanhoorelbeke, J. T. B. Crawley, J. Emsley
Summary: This study elucidates the molecular mechanisms behind the spatial conformational changes and global latency of ADAMTS13, providing important insights into the regulation of this metalloprotease's function.
Review
Biochemistry & Molecular Biology
Aranyak Mitra, Nandini Sarkar
Summary: All proteins have the ability to transform into amyloid fibrils under specific conditions. Disulfide bonds play a crucial role in modulating the propensity of protein aggregation. Intra-molecular disulfide bonds stabilize the native structure, while intermolecular disulfide bonds aid in the aggregation process. This review analyzes the effects of these bonds on the amyloid aggregation of proteins associated with amyloid disorders.
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2022)
Article
Crystallography
Ma Carmen Salinas-Garcia, Marina Plaza-Garrido, Jose A. A. Gavira, Javier Murciano-Calles, Montserrat Andujar-Sanchez, Emilia Ortiz-Salmeron, Jose C. C. Martinez, Ana Camara-Artigas
Summary: The PDZ domains can recognize short linear C-terminal sequences in proteins, facilitating the formation of complex multi-component structures. Crystals of the third PDZ domain of PSD95 were obtained at mildly acidic pH, resulting in four different polymorphs. The polymorphs exhibit different crystal shapes and share a common crystallographic interface. Analysis of these polymorphs provides insights into the importance of specific protein-protein interactions in protein crystallization.
Article
Biochemistry & Molecular Biology
Sebastian Fuehrer, Jana Unterhauser, Ricarda Zeindl, Reiner Eidelpes, Monica L. Fernandez-Quintero, Klaus R. Liedl, Martin Tollinger
Summary: PR-10 proteins are a major cause of food allergic reactions. This study analyzes the structural flexibility of thirteen PR-10 proteins from prevalent plant food sources and reveals that they have inherently flexible protein backbones in solution, with protein-specific extent of flexibility.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemical Research Methods
Xingyue Guan, Cheng Tan, Wenfei Li, Wei Wang, D. Thirumalai
Summary: This study reveals the crucial role of water-bridged interactions in metal ion coupled protein allostery, which reduces the ruggedness of ligand exchange landscape and facilitates allosteric communication. The asymmetric response of symmetrically arranged EF-hands upon Ca2+ binding is also highlighted as essential for efficient allosteric communication.
PLOS COMPUTATIONAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Eva S. Cobos, Ignacio E. Sanchez, Lucia B. Chemes, Jose C. Martinez, Javier Murciano-Calles
Summary: PDZ domains play a crucial role in cell signaling and cell-cell junctions, being able to recognize various natural targets. The study reveals a basic specificity in each PDZ domain, with host partners mostly being able to bind their corresponding PDZ domain. Additionally, viral ligands show the ability to bind most of the studied PDZ domains, including those not previously described.
Article
Biochemistry & Molecular Biology
Kei Segawa, Kazuhiko Igarashi, Kazutaka Murayama
Summary: The function of the transcription factor BACH1 is regulated by heme binding to multiple Cys-Pro (CP) motifs within its intrinsically disordered regions. The individual CP motifs contribute to the regulation of BACH1 activity by accepting heme in different coordination manners and their spatial locations are important for their individual functions. The presence of multiple CP motifs with distinct roles ensures the multifaceted, strict regulation of BACH1 by heme.
Article
Biochemistry & Molecular Biology
Gregory D. Martyn, Gianluca Veggiani, Ulrike Kusebauch, Seamus R. Morrone, Bradley P. Yates, Alex U. Singer, Jiefei Tong, Noah Manczyk, Gerald Gish, Zhi Sun, Igor Kurinov, Frank Sicheri, Michael F. Moran, Robert L. Moritz, Sachdev S. Sidhu
Summary: A comprehensive analysis of the phosphoproteome is crucial for understanding human diseases. Researchers have developed new SH2 domains with superior binding abilities to enrich diverse sets of phosphotyrosine peptides.
ACS CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Boglarka Zambo, Gergo Gogl, Bastien Morlet, Pascal Eberling, Luc Negroni, Herve Moine, Gilles Trave
Summary: This study comprehensively investigates the PDZ-PBM interactome of diacylglycerol kinases (DGKs) using interactomic approaches and evolutionary analysis, revealing functional differences between PBMs of different types of DGKs.
Article
Biochemistry & Molecular Biology
Kyle S. Gregory, Anna R. Newell, Otsile O. Mojanaga, Sai Man Liu, K. Ravi Acharya
Summary: This study determined the crystal structure of botulinum neurotoxin A6 cell binding domain (H-C/A6) in complex with GD1a and presented a new crystal form of wild type H-C/A6 (crystal form II), revealing the degree of conformational flexibility exhibited by H-C/A6.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Markus Schneider, Iris Antes
Summary: The study introduces a new protein structure network analysis framework SenseNet, which evaluates interaction timelines obtained by molecular dynamics simulations. The results show high accuracy in predicting allosteric residues in proteins, which is important for drug design research.
Article
Chemistry, Physical
Catherine Ghosh, Biman Jana
Summary: Metal ions, especially calcium, play crucial roles in cellular functions. This study investigates how calcium affects the conformation dynamics of calmodulin and its interaction with the target protein smMLCK. The findings suggest that while calcium-independent, calcium can regulate the binding site of smMLCK peptide on calmodulin.
JOURNAL OF PHYSICAL CHEMISTRY B
(2021)
Article
Multidisciplinary Sciences
Joanne L. Parker, Justin C. Deme, Gabriel Kuteyi, Zhiyi Wu, Jiandong Huo, I. David Goldman, Raymond J. Owens, Philip C. Biggin, Susan M. Lea, Simon Newstead
Summary: Folates, also known as vitamin B9, play a critical role in cellular metabolism and their deficiency is linked to various disorders. Mammals cannot synthesize folates and rely on uptake from the diet. The proton-coupled folate transporter is important for folate uptake and drug delivery.
Article
Biochemistry & Molecular Biology
Lucy Kate Ladefoged, Rebekka Koch, Philip C. Biggin, Birgit Schiott
Summary: Studying the action of multimodal antidepressant drug vortioxetine (VXT) on different receptors can provide insights into the mechanisms of agonist-antagonist dual behavior and activation without polar interaction with helix 5.
ACS CHEMICAL NEUROSCIENCE
(2022)
Article
Chemistry, Physical
Zhiyi Wu, Philip C. Biggin
Summary: Absolute binding free-energy calculations play a crucial role in drug design, but accuracy is of utmost importance. This study explores the most suitable approach for simulation boxes containing lipid bilayers, and introduces the Rocklin correction method for lipid bilayer systems.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Biochemistry & Molecular Biology
Harold Grosjean, Mehtap Isik, Anthony Aimon, David Mobley, John Chodera, Frank von Delft, Philip C. Biggin
Summary: A novel crystallographic fragment screening data set was generated and used in the SAMPL7 challenge for protein-ligands. The results show that there is room for improvement in the development of computational tools particularly when applied to fragment-based drug design.
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
(2022)
Article
Physiology
Adamo S. Mancino, William G. Glass, Yuhao Yan, Philip C. Biggin, Derek Bowie
Summary: Using electrophysiology and molecular dynamics simulations, this study highlights the role of two alternatively spliced residues in the DI S3-S4 linker in channel activation of Nav1.5 and suggests a conserved function in Nav1.4 isoform. Understanding the structural mechanisms of alternative splicing in gating properties of voltage-gated ion channels can provide insights into therapeutic target identification and drug development for related cardiac disorders.
JOURNAL OF GENERAL PHYSIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Tsung-Han Chou, Max Epstein, Kevin Michalski, Eve Fine, Philip C. Biggin, Hiro Furukawa
Summary: Excitatory signaling mediated by N-methyl-d-aspartate receptor (NMDAR) is critical for brain development and function, as well as for neurological diseases and disorders. Channel blockers of NMDARs are of medical interest owing to their potential for treating depression, Alzheimer's disease, and epilepsy. However, precise mechanisms underlying binding and channel blockade have remained limited owing to challenges in obtaining high-resolution structures at the binding site within the transmembrane domains.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2022)
Review
Physiology
David Seiferth, Philip C. Biggin, Stephen J. Tucker
Summary: This article discusses the hydrophobic gating mechanism in ion channels, which regulates ion permeation by controlling the wetness of the pore. The article provides a detailed definition of hydrophobic gating, compares it with other gating mechanisms, and describes the best practices for identifying a hydrophobic gate.
JOURNAL OF GENERAL PHYSIOLOGY
(2022)
Article
Multidisciplinary Sciences
Arvind Kumar, Kayla Kindig, Shanlin Rao, Afroditi-Maria Zaki, Sandip Basak, Mark S. P. Sansom, Philip C. Biggin, Sudha Chakrapani
Summary: This study reveals the structures of Glycine receptors (GlyRs) bound to Delta 9 -tetrahydrocannabinol (THC) using cryo-electron microscopy, providing insights into the therapeutic effects of cannabinoids.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Multidisciplinary
Irfan Alibay, Aniket Magarkar, Daniel Seeliger, Philip Charles Biggin
Summary: The authors evaluate the use of absolute binding free energy calculations in guiding fragment optimization decisions and find that such calculations can effectively guide fragment elaborations to maximize affinity.
COMMUNICATIONS CHEMISTRY
(2022)
Article
Chemistry, Physical
Simon M. Lichtinger, Philip C. Biggin
Summary: The structure of proteins holds the key to understanding their function, but studying the conformational transitions is challenging. The traditional molecular dynamics simulation suffers from starting-state dependence, while the new MEMENTO method provides a solution.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Multidisciplinary Sciences
Eric Gibbs, Emily Klemm, David Seiferth, Arvind Kumar, Serban L. Ilca, Philip C. Biggin, Sudha Chakrapani
Summary: In this study, cryo-EM structures of the α1βGlyR in the presence of an antagonist, agonist, and agonist with a positive allosteric modulator were determined. The structures revealed distinct pore conformations with varying degrees of asymmetry, and the receptors were found to be in closed or desensitized states. Subunit-specific features and characteristics of the extracellular and intracellular domains were also identified. These findings provide a framework for further investigations into the function of this physiologically important channel.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Medicinal
Suleyman Selim Cinaroglu, Philip C. Biggin
Summary: Understanding the thermodynamic signature of protein-peptide binding events is a major challenge in computational chemistry. This study computed the enthalpy of binding for protein-peptide complexes using available experimental data and identified key sampling problems that can be addressed to improve the agreement with experiments. The results show the potential of computational calorimetry in predicting protein-peptide binding enthalpy.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Multidisciplinary
Sueleyman Selim Cinaroglu, Philip C. C. Biggin
Summary: The enthalpic and entropic components of ligand-protein binding free energy are challenging to predict accurately. Recent advances in predicting relative and absolute binding free energies have been successful, but predicting the enthalpic contributions remains challenging. A study evaluating the performance of absolute enthalpy of binding calculations for inhibitors against a bromodomain protein showed good agreement with experimental data and revealed the importance of considering conformational dynamics of a specific loop in improving accuracy.
Article
Chemistry, Physical
David Seiferth, Stephen J. Tucker, Philip C. Biggin
Summary: Transmembrane anion transport by synthetic ionophores is important for understanding endogenous anion transport and has potential therapeutic implications. Computational studies using non-polarizable and polarizable force fields provide insights into the binding properties of anions. The results show solvent dependency and the importance of electrostatics and oxidation status in anion recognition.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2023)
Article
Chemistry, Multidisciplinary
Daniel Crusius, Jason R. Schnell, Flaviu Cipcigan, Philip C. Biggin
Summary: Knowing the solution structures of cyclic peptides is crucial for predicting the pharmacokinetic properties in drug discovery. In this study, we introduced the MacroConf dataset and computational workflows to evaluate the performance of current in silico methods in reproducing experimental cyclic peptide solution structures. Our findings show that enhanced sampling molecular dynamics methods, like Gaussian accelerated MD, performed well in reproducing experimental results. Conventional MD suffered from limited sampling, especially for compounds with proline isomerization. Cheminformatics-based conformer generators generated diverse and plausible structures that matched the sampling observed in MD-based methods, but did not provide thermodynamic insights. The presented computational workflow can be easily extended to include new compounds or different simulation methods, serving as a benchmark to improve cyclic peptide conformer generators.