Article
Biochemistry & Molecular Biology
Jose A. Amaya, David C. Lamb, Steven L. Kelly, Patrick Caffrey, Vidhi C. Murarka, Thomas L. Poulos
Summary: This study provides insights into the structural basis of substrate selectivity in the cytochrome P450 enzyme AmphL. A comparison with the closely related enzyme PimD reveals key catalytic structural features responsible for stereo- and regio-selective oxidation. The study also highlights the role of additional substrate interactions and -OH groups in correctly positioning the substrate and activating O-2. This research could contribute to the development of new macrolide antibiotics with enhanced antifungal and/or antiprotozoal efficacy.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Juan Huang, Qin Xu, Zhuo Liu, Nitin Jain, Madhusudan Tyagi, Dong-Qing Wei, Liang Hong
Summary: This study found that the high density of salt bridges in CYP450 proteins reduces structural flexibility, affecting substrate selection and catalytic activity. By making slight chemical changes, the CYP450 superfamily can regulate the structural flexibility of its member proteins to differentiate substrate specificities.
Article
Chemistry, Applied
Yue Yuan, Hui Li, Wellington Leite, Qiu Zhang, Peter Bonnesen, Jessy L. Labbe, Kevin L. Weiss, Sai Venkatesh Pingali, Kunlun Hong, Volker S. Urban, Sonja Salmon, Hugh O'Neill
Summary: Deuterated chitosan was produced using deuterated glucose, with NMR and SANS analysis revealing its structure and chemical composition. This highly deuterated chitosan can be used as a model material for studying chitosan-enzyme complexes in neutron scattering studies.
CARBOHYDRATE POLYMERS
(2021)
Article
Chemistry, Physical
Wenke Mueller, Ralf Schweins, Bernd Noecker, Hans Egold, Klaus Huber
Summary: The complexity of intermolecular interactions and the difficulty to predict assembly behaviour solely based on chemical constitution were demonstrated by studying the self-assembly of three one-fold negatively charged 3-chloro-4-hydroxy-phenylazo dyes (Yellow, Blue and Red). Differences in dye self-assembly were observed, with Yellow not self-assembling, Red forming higher-order aggregates, and Blue forming well-defined H-aggregate dimers with a dimerization constant of Kd = (728 +/- 8) L mol(-1). These differences were suggested to arise from variations in the propensity to form pi-pi interactions due to electrostatic repulsion, sterical constraints and hydrogen-bonding interactions.
Article
Chemistry, Multidisciplinary
Adrian Gonzalez-Nelson, Srinidhi Mula, Mantas Simenas, Sergejus Balciunas, Adam R. Altenhof, Cameron S. Vojvodin, Stefano Canossa, Juras Banys, Robert W. Schurko, Francois-Xavier Coudert, Monique A. van der Veen
Summary: The organic components in MOFs exhibit unique dynamic behavior, with the rotation of organic linkers playing a crucial role in determining their properties. By modifying the structure and environment of the linkers, the rotation speed and mode can be controlled to achieve function-specific cooperative motion.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Biochemistry & Molecular Biology
Christopher S. Campomizzi, George E. Ghanatios, D. Fernando Estrada
Summary: Cytochromes P450 are versatile enzymes involved in endogenous and exogenous metabolism, undergoing structural changes related to function. This study demonstrates the utility of fluorine (19F)-NMR spectroscopy in monitoring structural changes in CYP121A1, revealing insights into its role in substrate recognition and mechanistic details of this essential enzyme from Mycobacterium tuberculosis.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Physics, Nuclear
Shingo Tagami, Tomotsugu Wakasa, Jun Matsui, Masanobu Yahiro, Maya Takechi
Summary: The study demonstrates good agreement between experimental data and theoretical models within a specific energy range, allowing for fine-tuning of parameters to accurately reproduce experimental data. Analysis of specific scattering reactions can provide precise inference of neutron radii.
Article
Materials Science, Multidisciplinary
R. Boffy, L. Martel, R. Schweins, J. Somers, J. Beaucour, F. J. Bermejo
Summary: The internal structure of several alkali-borosilicate glasses when exposed to a high thermal neutron flux was studied, with different glasses showing varying resistance to irradiation. Experimental tools like Nuclear Magnetic Resonance (NMR) and Small Angle Neutron Scattering (SANS) were used for structural analysis, revealing the possibility of phase segregation in a zinc-alkali-borosilicate.
JOURNAL OF NUCLEAR MATERIALS
(2021)
Article
Biochemistry & Molecular Biology
Yilin Liu, Ilia Denisov, Michael Gregory, Stephen G. Sligar, James R. Kincaid
Summary: This study investigates the impact of a CYP17A1 gene mutation on its catalytic activity. The results show that the mutation alters the lyase efficiency by affecting H-bonding interactions and protonation of the reactive ferric peroxo intermediate. The key reaction intermediates are successfully trapped and structurally characterized using cryoradiolysis and resonance Raman techniques.
Article
Physics, Multidisciplinary
Jieun Kim, Abinash Kumar, Yubo Qi, Hiroyuki Takenaka, Philip J. Ryan, Derek Meyers, Jong-Woo Kim, Abel Fernandez, Zishen Tian, Andrew M. Rappe, James M. LeBeau, Lane W. Martin
Summary: This study stabilizes the intermediate step during polarization rotation in relaxor ferroelectric materials using epitaxial strain and investigates the co-evolution of polarization and polar nanodomains. The findings establish the structural transitions between polar nanodomain configurations as the basis for the polarization rotation and large electromechanical coupling in relaxors.
Article
Chemistry, Physical
Mark Louis P. Vidallon, Luke W. Giles, Matthew J. Pottage, Calum S. G. Butler, Simon A. Crawford, Alexis Bishop, Rico F. Tabor, Liliana de Campo, Boon Mian Teo
Summary: The study utilized neutron scattering techniques to observe the phase transition of polydopamine-shelled perfluorocarbon emulsion droplets into microbubbles upon heating, showing that the transition temperatures are higher than the boiling points of pure liquid perfluorocarbons. Analysis and model fitting of neutron scattering data allowed monitoring of droplet size distributions at different temperatures, providing valuable insights into the transformation of these emulsion droplet systems.
JOURNAL OF COLLOID AND INTERFACE SCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Takahide Yamaguchi, Kouhei Akao, Alexandros Koutsioubas, Henrich Frielinghaus, Takamitsu Kohzuma
Summary: The dynamic structure changes of Cyt c & PRIME;, including unfolding, dimerization, and transition to an open-bundle structure, were investigated by small-angle neutron scattering experiment. The transition from compactly folded to an open-bundle structure at higher pH was confirmed through numerical analysis and ab initio modeling.
Article
Polymer Science
Magdalena Witek, Maciej Krzystyniak, Giovanni Romanelli, Teresa Witczak
Summary: This study utilizes a combination of experimental techniques to investigate the glass transition of dry rice pasta, revealing its nearly completely amorphous nature, with the glass transition occurring between 40 and 60 degrees Celsius. Changes in the secondary structure of starch within the pasta, along with partial loss of long-range order provided by the polymer structure, are also observed during the transition.
Article
Biochemistry & Molecular Biology
Xiaoyu Chen, Yue Ding, Rebecca S. Bamert, Anton P. Le Brun, Anthony P. Duff, Chun-Ming Wu, Hsien-Yi Hsu, Takuya Shiota, Trevor Lithgow, Hsin-Hui Shen
Summary: Researchers reconstituted each subunit of the Gram-negative bacteria BAM complex into a biomimetic membrane to study their interactions and structural changes. They found that binding of BamE or a BamDE dimer to BamA induced conformational changes, and addition of an unfolded substrate protein extended the length of POTRA domains as part of the mechanism for protein folding into the membrane.
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
(2021)
Article
Chemistry, Physical
Sajan Kumar, Mayanak K. Gupta, Prabhatasree Goel, Ranjan Mittal, Sanghamitra Mukhopadhyay, Manh Duc Le, Rakesh Shukla, Srungarpu N. Achary, Avesh K. Tyagi, Samrath L. Chaplot
Summary: We investigated the atomic dynamics and Li+ diffusion in crystalline and amorphous Li2Si2O5 using techniques such as quasielastic neutron scattering (QENS), inelastic neutron scattering (INS), and ab initio molecular dynamics simulations (AIMD). Our findings show that in the amorphous phase of Li2Si2O5, there is a narrow temperature range (700 < T < 775 K) where fast Li+ diffusion occurs, as evidenced by significant quasielastic broadening observed in the QENS measurements. The presence of low-energy phonon density of states (PDOS) in the superionic amorphous phase, which disappears in the non-superionic crystalline phase, further supports the role of low-energy modes in Li+ diffusion. AIMD simulations revealed that these low-energy modes involve large amplitude vibrations of Li coupled with SiO4 vibrations in the amorphous phase. At higher temperatures, these vibrational dynamics contribute to accelerated Li+ diffusion. Above 775 K, the SiO4 vibrational dynamics drive the system into the crystalline phase by locking SiO4 and Li+ into deeper minima of the free energy landscape, causing them to disappear in the crystalline phase. Both experiments and simulations provide valuable insights into the atomic-level stochastic and vibrational dynamics in Li2Si2O5 and their implications for Li+ diffusion and vitrification.
JOURNAL OF MATERIALS CHEMISTRY A
(2023)
Article
Chemistry, Physical
Jinan Wang, Yinglong Miao
Summary: Protein-protein interactions (PPIs) are crucial for many biological processes, but simulating the repetitive association and dissociation of proteins has been challenging. Researchers have developed a new computational approach, PPI-GaMD, based on Gaussian accelerated molecular dynamics (GaMD) technique, to calculate the binding free energies and kinetics of PPIs. The method has been validated on a model system and successfully simulated repetitive dissociation and rebinding events of proteins.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Chemistry, Physical
Frederic Celerse, Theo Jaffrelot Inizan, Louis Lagardere, Olivier Adjoua, Pierre Monmarche, Yinglong Miao, Etienne Derat, Jean-Philip Piquemal
Summary: The study presents a novel multilevel enhanced sampling strategy based on GaMD, implementing GaMD multi-GPU acceleration and dual-water mode in Tinker-HP to speed up solvent-solute interactions. By coupling GaMD with Umbrella Sampling, the convergence time of PMF is reduced significantly, and the introduction of Adaptive Sampling further enhances convergence speed, making it applicable for large-scale biological system simulations.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Biochemistry & Molecular Biology
Hung N. Do, Allan Haldane, Ronald M. Levy, Yinglong Miao
Summary: In this study, novel sequence coevolutionary models of A and B classes of GPCRs were constructed to compare and reveal important information about GPCR activation and allosteric modulation through examining residue contacts. The findings provide a promising framework for rational design of ligands to regulate GPCR activation and allosteric modulation.
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
(2022)
Article
Chemistry, Physical
Hung N. Do, Jinan Wang, Apurba Bhattarai, Yinglong Miao
Summary: We introduce a workflow called Gaussian-accelerated molecular dynamics (GaMD), deep learning (DL), and free energy profiling (GLOW) to predict molecular determinants and map free energy landscapes of biomolecules. This approach involves performing GaMD-enhanced sampling simulations, calculating structural contact maps, building DL models using a convolutional neural network, determining important structural contacts, and calculating free energy profiles. GLOW has been successfully used to characterize activation and allosteric modulation of a G protein-coupled receptor, providing mechanistic insights into its function.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Biochemistry & Molecular Biology
Viswanathan Gurumoorthy, Utsab R. Shrestha, Qiu Zhang, Sai Venkatesh Pingali, Eric T. Boder, Volker S. Urban, Jeremy C. Smith, Loukas Petridis, Hugh O'Neill
Summary: c-Src kinase is a non-receptor tyrosine kinase that phosphorylates signaling proteins in cancers. This study focuses on the N-terminal disordered region (SH4UD) and its interactions with other domains of c-Src kinase. The results show that the presence of SH4UD leads to structural changes in the regulatory domains (SH3-SH2), indicating the importance of the disordered region for allosteric interactions. This study provides insights that may aid in the development of therapeutic interventions targeting the regulatory domains of c-Src kinase.
Article
Chemistry, Physical
Jinan Wang, Yinglong Miao
Summary: This study presents LiGaMD2, an improved method for sampling ligand binding and dissociation by applying a selective boost potential to both the ligand and protein residues in the binding pocket. LiGaMD2 efficiently captured repetitive ligand dissociation and binding in microsecond simulations and produced accurate ligand binding kinetics and free energy values. Therefore, LiGaMD2 provides an efficient approach for calculating ligand binding thermodynamics and kinetics.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Chemistry, Multidisciplinary
Luoxi Tan, Haden L. Scott, Micholas Dean Smith, Sai Venkatesh Pingali, Hugh M. O'Neill, Jennifer L. Morrell-Falvey, John Katsaras, Jeremy C. Smith, Brian H. Davison, James G. Elkins, Jonathan D. Nickels
Summary: Biofuels are crucial for sustainable energy and optimizing their production is a societal and economic imperative. Reducing the toxicity of co-solvents can improve the efficiency of biofuel production.
ACS SUSTAINABLE CHEMISTRY & ENGINEERING
(2023)
Article
Chemistry, Physical
Mood Mohan, Micholas Dean Smith, Omar Demerdash, Michelle K. Kidder, Jeremy C. Smith
Summary: Understanding the physical properties of ionic liquids is crucial for various industrial and research applications, but experimental screening can be challenging and expensive. Previous research has shown that combining quantum-mechanics-based property prediction tools with machine learning approaches can help screen and design ionic liquids with desired properties. However, the most appropriate machine learning approach is still unclear.
JOURNAL OF CHEMICAL PHYSICS
(2023)
Review
Chemistry, Physical
Jinan Wang, Hung N. Do, Kushal Koirala, Yinglong Miao
Summary: Biomolecular binding kinetics, including association and dissociation rates, are crucial for the design of therapeutic drugs. The drug molecule's residence time or dissociation rate has shown a better correlation with efficacy compared to binding affinities. Various modeling approaches, such as structure-kinetic relationship models, molecular dynamics simulations, enhanced sampling, and machine learning, have been developed to explore biomolecular binding mechanisms and predict binding rates. In this review, we discuss recent advancements in computational modeling of biomolecular binding kinetics and the potential for future improvements.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Chemistry, Physical
Hung N. Do, Yinglong Miao
Summary: We have developed a new deep boosted molecular dynamics (DBMD) method that uses probabilistic Bayesian neural network models to construct boost potentials for accurate energetic reweighting and enhanced sampling of molecular simulations. The DBMD method was successfully applied to alanine dipeptide, fast-folding proteins, and RNA structures, achieving improved sampling and reproducing accurate free energy profiles. DBMD also showed the capability to capture folding pathways and identify low-energy conformations in simulations of protein and RNA systems.
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Physical
Shristi Pawnikar, Apurba Bhattarai, S. Xiaohu Ouyang, Ramir Vega, Yuan Chen, Yinglong Miao
Summary: Post-translational modifications by small ubiquitin-like modifiers (SUMOs) are dysregulated in many types of cancers. The SUMO E1 enzyme has recently been suggested as a new immuno-oncology target. COH000 was identified as an allosteric covalent inhibitor of SUMO E1, but there were inconsistencies between its X-ray structure and the structure-activity relationship (SAR) data of inhibitor analogues. By conducting Ligand Gaussian accelerated molecular dynamics (LiGaMD) simulations, we uncovered a critical non-covalent binding intermediate of COH000 that agreed well with published and new SAR data, resolving the discrepancy.
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Multidisciplinary
Mood Mohan, Micholas Dean Smith, Omar N. Demerdash, Blake A. Simmons, Seema Singh, Michelle K. Kidder, Jeremy C. Smith
Summary: Ionic liquids (ILs) have unique solvent properties, but it is unrealistic to experimentally determine their physicochemical properties. To address this issue, we developed machine learning models to predict the surface tension and speed of sound of ILs, which showed excellent agreement with experimental observations. This study paves the way for the development of machine learning models for predicting IL properties.
ACS SUSTAINABLE CHEMISTRY & ENGINEERING
(2023)
Article
Chemistry, Physical
Shristi Pawnikar, Apurba Bhattarai, S. Xiaohu Ouyang, Ramir Vega, Yuan Chen, Yinglong Miao
Summary: Through novel Ligand Gaussian accelerated molecular dynamics (LiGaMD) simulations, we have identified a critical low-energy non-covalent binding intermediate conformation of COH000 that agrees excellently with published and new structure-activity relationship (SAR) data of COH000 analogues, which are inconsistent with the X-ray structure. Our biochemical experiments and LiGaMD simulations have uncovered a critical non-covalent binding intermediate during allosteric inhibition of the SUMO E1 complex.
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Medicinal
Rupesh Agarwal, T. Rajitha Rajeshwar, Jeremy C. Smith
Summary: Structure-based virtual high-throughput screening is commonly used in early-stage drug discovery. This study evaluated the performance of three docking protocols on 173 RNA-small molecule crystal structures. The results showed that Vina and rDock are both applicable for projects without known ligand-protein structures, but their performance is relatively poor compared to protein-target docking methods.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Biochemistry & Molecular Biology
Jinan Wang, Lan Lan, Xiaoqing Wu, Liang Xu, Yinglong Miao
Summary: The Musashi RNA-binding proteins play important roles in regulating mRNA translation, cell stemness, and tumorigenesis. Musashi-1 (MSI1), previously known as an intestinal and neural stem cell marker, has been found to be overexpressed in many cancers and is a significant drug target for acute myeloid leukemia and solid tumors. In this study, researchers utilized all-atom microsecond-timescale simulations to investigate the dynamic mechanism of Numb RNA binding to MSI1. Their simulations revealed important intermediate conformational states during RNA binding and provide insight for structure-based drug design targeting MSI1 and other RBPs.
CURRENT RESEARCH IN STRUCTURAL BIOLOGY
(2022)