Article
Biology
Aayush Gupta, Souvik Dey, Alan Hicks, Huan-Xiang Zhou
Summary: This study developed generative autoencoders that can learn from short molecular dynamics simulations and generate full conformational ensembles of intrinsically disordered proteins.
COMMUNICATIONS BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Rajeswari Appadurai, Jayashree Nagesh, Anand Srivastava
Summary: The study introduces a parallel-tempering method that utilizes accelerated water dynamics for efficient and accurate conformational sampling across a wide variety of proteins, demonstrating successful application to large metamorphic proteins and highly disordered proteins with good fit to experimental data.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Medicinal
Xiaoyue Ji, Hao Liu, Yangpeng Zhang, Jun Chen, Hai-Feng Chen
Summary: Intrinsically disordered proteins (IDPs) are associated with various diseases and molecular dynamics simulations can provide valuable information to complement experimental data for IDPs. However, current force fields cannot accurately reproduce the conformation of IDPs. To address this issue, researchers used deep learning and reweighting methods to generate personalized force field parameters for IDPs. The results showed that these parameters could better replicate experimental observables, offering feasibility for the development of precise personal force fields.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Medicinal
Ryuhei Harada, Rikuri Morita, Yasuteru Shigeta
Summary: The free-energy profile of a compound is crucial in evaluating membrane permeation and can be calculated using molecular dynamics simulations. However, existing methods often fail to sample rare events in membrane permeation accurately. In this study, a hybrid conformational search method combining rare-event sampling methods and Markov state models was proposed to calculate the free-energy profiles and membrane permeability of seven compounds with good correlation to experimental measurements.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Physical
Rajeswari Appadurai, Jaya Krishna Koneru, Massimiliano Bonomi, Paul Robustelli, Anand Srivastava
Summary: In this study, t-SNE technique is used to cluster the conformations of intrinsically disordered proteins (IDPs) and visualize the conformational heterogeneity. The conformations of two disordered proteins, Aβ42 and α-synuclein, in their APO states and when bound to small molecule ligands are analyzed, revealing ordered substates within the IDP ensembles and providing insights into the structural and mechanistic aspects of IDP ligand binding. t-SNE projections preserve local neighborhood information, providing interpretable visualizations of conformational heterogeneity within each ensemble and allowing the quantification of cluster populations and their relative shifts upon ligand binding.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Chemistry, Physical
Abhishek Acharya, Jigneshkumar Dahyabhai Prajapati, Ulrich Kleinekathoefer
Summary: Understanding the molecular mechanisms underlying the transport of antibiotics into bacterial cells is crucial for the development of effective antibacterial drugs. Accurate determination of free energy surfaces for antibiotic translocation is necessary for meaningful comparisons between different classes of antibiotics. Two sampling methods combining umbrella sampling and metadynamics-style biasing schemes with temperature acceleration have been employed to improve sampling and convergence in this study, showing promising results for the ciprofloxacin-OmpF system.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2021)
Article
Chemistry, Physical
Wenning Wang
Summary: Recent progress in atomic MD simulation studies of intrinsically disordered proteins (IDPs) includes the development of force fields and sampling methods, as well as applications in IDP-involved protein-protein interactions. Large-scale simulations and advanced sampling techniques allow for a more accurate estimation of the thermodynamics and kinetics of IDP-mediated protein interactions. The holistic landscape of the binding process of IDPs is emerging through these simulations.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2021)
Article
Multidisciplinary Sciences
Kulkarni Madhurima, Bodhisatwa Nandi, Sneha Munshi, Athi N. Naganathan, Ashok Sekhar
Summary: The structure of a thermally accessible excited state in equilibrium with the native ensemble of a bacterial transcriptional regulator CytR has been determined using multinuclear CEST NMR. Evidence from double resonance CEST experiments suggests that the excited state, which resembles the DNA-bound form of CytR, recognizes DNA through a folding-before-binding conformational selection pathway. The disorder-to-order regulatory switch in DNA recognition by natively disordered CytR operates through a dynamical variant of the lock-and-key mechanism.
Article
Chemistry, Physical
Pandurangan Kalipillai, E. Raghuram, Ethayaraja Mani
Summary: The inhibitory effect of negatively charged gold nanoparticles (AuNPs) on amyloidogenic protein fibrillation has been investigated through experiments and simulations. The charge density of gold (Au) surfaces was found to affect the adsorption of amyloid beta 40 (Aβ40) monomer, with specific residues responsible for preventing beta-sheet formation. The study suggests that an optimal charge density on the surface is necessary to effectively inhibit fibrillation.
Article
Chemistry, Physical
Srinivasa M. Gopal, Sebastian Wingbermuehle, Jan Schnatwinkel, Selina Juber, Christian Herrmann, Lars Schaefer
Summary: Molecular simulations of intrinsically disordered proteins pose challenges due to the need to sample a large number of shallow minima on a flat free energy landscape. In the presence of a binding partner, the free energy landscape is dominated by deep minima, requiring accurate force fields for molecular interactions. The study compared six modern biomolecular force fields in describing the structural ensembles of the c-Myb transactivation domain, with some force fields showing promise for future simulation studies.
JOURNAL OF PHYSICAL CHEMISTRY B
(2021)
Article
Chemistry, Medicinal
Karnesh Jain, Othman Ghribi, Jerome Delhommelle
Summary: The misfolding and aggregation of alpha-synuclein play a crucial role in neurodegenerative disorders, with the formation of fibrils involving various intermediates. Simulation results show that conformational rearrangements of alpha-synuclein at physiological temperature mainly exhibit alpha-helix structures. These findings provide valuable insights for understanding the formation of oligomers in neurodegenerative diseases.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Biochemistry & Molecular Biology
Shangbo Ning, Hong-Jun Chao, Shuangli Li, Rui Zhou, Lei Zou, Xu Zhang, Jun Liu, Dazhong Yan, Mojie Duan
Summary: This study investigates the molecular mechanism of phosphorylation regulation on the auto-inhibition of Ets-1 using molecular simulations and biochemical experiments. The results suggest that both steric hindrance and allosteric regulation are involved in the DNA-binding inhibitory effect caused by phosphorylation, with steric effects playing a greater role.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2022)
Article
Chemistry, Physical
Valerio Rizzi, Simone Aureli, Narjes Ansari, Francesco Luigi Gervasio
Summary: Enhanced sampling techniques, such as using collective variables (CVs) or parallel tempering, have greatly advanced molecular dynamics simulations for studying rare events and calculating free energy differences. We propose a replica exchange method called OneOPES that combines the advantages of multireplica simulations and CV-based enhanced sampling, providing an efficient and robust framework for complex systems.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Biochemical Research Methods
Balint Meszaros, Andras Hatos, Nicolas Palopoli, Federica Quaglia, Edoardo Salladini, Kim Van Roey, Haribabu Arthanari, Zsuzsanna Dosztanyi, Isabella C. Felli, Patrick D. Fischer, Jeffrey C. Hoch, Cy M. Jeffries, Sonia Longhi, Emiliano Maiani, Sandra Orchard, Rita Pancsa, Elena Papaleo, Roberta Pierattelli, Damiano Piovesan, Iva Pritisanac, Luiggi Tenorio, Thibault Viennet, Peter Tompa, Wim Vranken, Silvio C. E. Tosatto, Norman E. Davey
Summary: This Perspective introduces the Minimum Information About Disorder Experiments guidelines, which provide a community consensus on the minimum information required to appropriately describe metadata on experimentally and computationally derived structural state(s) of intrinsically disordered proteins or regions. An unambiguous description of an experiment, and the subsequent biological observation, is vital for accurate data interpretation.
Review
Biochemistry & Molecular Biology
Matthew A. H. Parson, Meredith L. Jenkins, John E. Burke
Summary: This review discusses the application of Hydrogen-deuterium exchange mass spectrometry (HDX-MS) as a powerful biophysical tool for studying the structure and function of intrinsically disordered regions in proteins. The focus is on the theory of hydrogen exchange and its practical application in identifying disordered regions and characterizing their involvement in protein-protein and protein-membrane interfaces.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2022)
Article
Biophysics
Cayla M. Miller, Young C. Kim, Jeetain Mittal
BIOPHYSICAL JOURNAL
(2016)
Article
Chemistry, Physical
Robert B. Best, Cayla Miller, Jeetain Mittal
JOURNAL OF CHEMICAL PHYSICS
(2014)
Article
Chemistry, Physical
Cayla Miller, Guel H. Zerze, Jeetain Mittal
JOURNAL OF PHYSICAL CHEMISTRY B
(2013)
Article
Chemistry, Physical
Cayla M. Miller, Angela C. Brown, Jeetain Mittal
JOURNAL OF PHYSICAL CHEMISTRY B
(2014)
Article
Multidisciplinary Sciences
Steven J. Tan, Alice C. Chang, Cayla M. Miller, Sarah M. Anderson, Louis S. Prahl, David J. Odde, Alexander R. Dunn
Article
Multidisciplinary Sciences
Cayla M. Miller, Elgin Korkmazhan, Alexander R. Dunn
Summary: This study presents a method to extract actin filament velocities in living cells and compares them to current models of cytoskeletal dynamics. The authors found that the motion of actin filaments is better described by a statistical jump process than continuous, diffusive movement models. This suggests that a common physical model can potentially explain actin filament dynamics in various cellular contexts.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Miguel A. Ramirez, Yuzuru Ninoyu, Cayla Miller, Leonardo R. Andrade, Seby Edassery, Ewa Bomba-Warczak, Briana Ortega, Uri Manor, Mark A. Rutherford, Rick A. Friedman, Jeffrey N. Savas
Summary: This study found that neuroligins play a crucial role in the formation and function of synapses in the cochlea, with Nlgn3 and Nlgn1 knockout leading to a decrease in the number of ribbon synapses in the cochlea, impacting hearing.