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922 results on '"Mulholland, Adrian J."'

54. Decrypting Allostery in Membrane-Bound K-Ras4B Using Complementary In SilicoApproaches Based on Unbiased Molecular Dynamics Simulations

Author

Castelli, Matteo, Marchetti, Filippo, Osuna, Sílvia, F. Oliveira, A. Sofia, Mulholland, Adrian J., Serapian, Stefano A., and Colombo, Giorgio

Abstract

Protein functions are dynamically regulated by allostery, which enables conformational communication even between faraway residues, and expresses itself in many forms, akin to different “languages”: allosteric control pathways predominating in an unperturbed protein are often unintuitively reshaped whenever biochemical perturbations arise (e.g., mutations). To accurately model allostery, unbiased molecular dynamics (MD) simulations require integration with a reliable method able to, e.g., detect incipient allosteric changes or likely perturbation pathways; this is because allostery can operate at longer time scales than those accessible by plain MD. Such methods are typically applied singularly, but we here argue their joint application─as a “multilingual” approach─could work significantly better. We successfully prove this through unbiased MD simulations (∼100 μs) of the widely studied, allosterically active oncotarget K-Ras4B, solvated and embedded in a phospholipid membrane, from which we decrypt allostery using four showcase “languages”: Distance Fluctuationanalysis and the Shortest Path Mapcapture allosteric hotspots at equilibrium; Anisotropic Thermal Diffusionand Dynamical Non-Equilibrium MD simulationsassess perturbations upon, respectively, either superheating or hydrolyzing the GTP that oncogenically activates K-Ras4B. Chosen “languages” work synergistically, providing an articulate, mutually coherent, experimentally consistent picture of K-Ras4B allostery, whereby distinct traits emerge at equilibrium and upon GTP cleavage. At equilibrium, combined evidence confirms prominent allosteric communication from the membrane-embedded hypervariable region, through a hub comprising helix α5 and sheet β5, and up to the active site, encompassing allosteric “switches” I and II (marginally), and two proposed pockets. Upon GTP cleavage, allosteric perturbations mostly accumulate on the switches and documented interfaces.

Published
2024
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61. #COVIDisAirborne: AI-enabled multiscale computational microscopy of delta SARS-CoV-2 in a respiratory aerosol

Author

Dommer, Abigail, primary, Casalino, Lorenzo, additional, Kearns, Fiona, additional, Rosenfeld, Mia, additional, Wauer, Nicholas, additional, Ahn, Surl-Hee, additional, Russo, John, additional, Oliveira, Sofia, additional, Morris, Clare, additional, Bogetti, Anthony, additional, Trifan, Anda, additional, Brace, Alexander, additional, Sztain, Terra, additional, Clyde, Austin, additional, Ma, Heng, additional, Chennubhotla, Chakra, additional, Lee, Hyungro, additional, Turilli, Matteo, additional, Khalid, Syma, additional, Tamayo-Mendoza, Teresa, additional, Welborn, Matthew, additional, Christensen, Anders, additional, Smith, Daniel GA, additional, Qiao, Zhuoran, additional, Sirumalla, Sai K, additional, O’Connor, Michael, additional, Manby, Frederick, additional, Anandkumar, Anima, additional, Hardy, David, additional, Phillips, James, additional, Stern, Abraham, additional, Romero, Josh, additional, Clark, David, additional, Dorrell, Mitchell, additional, Maiden, Tom, additional, Huang, Lei, additional, McCalpin, John, additional, Woods, Christopher, additional, Gray, Alan, additional, Williams, Matt, additional, Barker, Bryan, additional, Rajapaksha, Harinda, additional, Pitts, Richard, additional, Gibbs, Tom, additional, Stone, John, additional, Zuckerman, Daniel M., additional, Mulholland, Adrian J., additional, Miller, Thomas, additional, Jha, Shantenu, additional, Ramanathan, Arvind, additional, Chong, Lillian, additional, and Amaro, Rommie E, additional

Published
2022
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68. Virtual Screening Identifies Novel and Potent Inhibitors of Mycobacterium tuberculosis PknB with Antibacterial Activity

Author

Thongdee, Paptawan, primary, Hanwarinroj, Chayanin, additional, Pakamwong, Bongkochawan, additional, Kamsri, Pharit, additional, Punkvang, Auradee, additional, Leanpolchareanchai, Jiraporn, additional, Ketrat, Sombat, additional, Saparpakorn, Patchreenart, additional, Hannongbua, Supa, additional, Ariyachaokun, Kanchiyaphat, additional, Suttisintong, Khomson, additional, Sureram, Sanya, additional, Kittakoop, Prasat, additional, Hongmanee, Poonpilas, additional, Santanirand, Pitak, additional, Mukamolova, Galina V., additional, Blood, Rosemary A., additional, Takebayashi, Yuiko, additional, Spencer, James, additional, Mulholland, Adrian J., additional, and Pungpo, Pornpan, additional

Published
2022
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76. Discovery of novel and potent InhA inhibitors by an in silico screening and pharmacokinetic prediction

Author

Hanwarinroj, Chayanin, primary, Phusi, Nareudon, additional, Kamsri, Bundit, additional, Kamsri, Pharit, additional, Punkvang, Auradee, additional, Ketrat, Sombat, additional, Saparpakorn, Patchreenart, additional, Hannongbua, Supa, additional, Suttisintong, Khomson, additional, Kittakoop, Prasat, additional, Spencer, James, additional, Mulholland, Adrian J, additional, and Pungpo, Pornpan, additional

Published
2022
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80. Identification of Potent DNA Gyrase Inhibitors Active against Mycobacterium tuberculosis

Author

Pakamwong, Bongkochawan, primary, Thongdee, Paptawan, additional, Kamsri, Bundit, additional, Phusi, Naruedon, additional, Kamsri, Pharit, additional, Punkvang, Auradee, additional, Ketrat, Sombat, additional, Saparpakorn, Patchreenart, additional, Hannongbua, Supa, additional, Ariyachaokun, Kanchiyaphat, additional, Suttisintong, Khomson, additional, Sureram, Sanya, additional, Kittakoop, Prasat, additional, Hongmanee, Poonpilas, additional, Santanirand, Pitak, additional, Spencer, James, additional, Mulholland, Adrian J., additional, and Pungpo, Pornpan, additional

Published
2022
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83. A Community Letter Regarding Sharing Biomolecular Simulation Data for COVID-19

Author

Amaro, Rommie E. and Mulholland, Adrian J.

Subjects
2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Computer science, General Chemical Engineering, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Pneumonia, Viral, Information Dissemination, Library and Information Sciences, Models, Biological, 01 natural sciences, Betacoronavirus, Viewpoint, Artificial Intelligence, 0103 physical sciences, Humans, Viral therapy, Pandemics, 010304 chemical physics, SARS-CoV-2, COVID-19, Computational Biology, General Chemistry, computer.file_format, Data science, 0104 chemical sciences, Computer Science Applications, Test (assessment), shar, 010404 medicinal & biomolecular chemistry, Coronavirus Infections, computer, Algorithms, Software
Abstract

There is an urgent need to share our methods, models, and results openly and quickly to test findings, ensure reproducibility, test significance, eliminate dead-ends, and accelerate discovery. Shar...

Published
2020

84. Interactivity:the missing link between virtual reality technology and drug discovery pipelines

Author

Walters, Rebecca K., Gale, Ella M., Barnoud, Jonathan, Glowacki, David R., and Mulholland, Adrian J.

Subjects
q-bio.BM
Abstract

The potential of virtual reality (VR) to contribute to drug design and development has been recognised for many years. Hardware and software developments now mean that this potential is beginning to be realised, and VR methods are being actively used in this sphere. A recent advance is to use VR not only to visualise and interact with molecular structures, but also to interact with molecular dynamics simulations of 'on the fly' (interactive molecular dynamics in VR, IMD-VR), which is useful not only for flexible docking but also to examine binding processes and conformational changes. iMD-VR has been shown to be useful for creating complexes of ligands bound to target proteins, e.g., recently applied to peptide inhibitors of the SARS-CoV-2 main protease. In this review, we use the term 'interactive VR' to refer to software where interactivity is an inherent part of the user VR experience e.g., in making structural modifications or interacting with a physically rigorous molecular dynamics (MD) simulation, as opposed to simply using VR controllers to rotate and translate the molecule for enhanced visualisation. Here, we describe these methods and their application to problems relevant to drug discovery, highlighting the possibilities that they offer in this arena. We suggest that the ease of viewing and manipulating molecular structures and dynamics, and the ability to modify structures on the fly (e.g., adding or deleting atoms) makes modern interactive VR a valuable tool to add to the armoury of drug development methods.

Published
2022

86. Interactive molecular dynamics in virtual reality from quantum chemistry to drug binding: An open-source multi-person framework.

Author

O'Connor, Michael B., Bennie, Simon J., Deeks, Helen M., Jamieson-Binnie, Alexander, Jones, Alex J., Shannon, Robin J., Walters, Rebecca, Mitchell, Thomas J., Mulholland, Adrian J., and Glowacki, David R.

Subjects
QUANTUM chemistry, MOLECULAR dynamics, PHARMACEUTICAL chemistry, VIRTUAL reality, NANOTECHNOLOGY
Abstract

As molecular scientists have made progress in their ability to engineer nanoscale molecular structure, we face new challenges in our ability to engineer molecular dynamics (MD) and flexibility. Dynamics at the molecular scale differs from the familiar mechanics of everyday objects because it involves a complicated, highly correlated, and three-dimensional many-body dynamical choreography which is often nonintuitive even for highly trained researchers. We recently described how interactive molecular dynamics in virtual reality (iMD-VR) can help to meet this challenge, enabling researchers to manipulate real-time MD simulations of flexible structures in 3D. In this article, we outline various efforts to extend immersive technologies to the molecular sciences, and we introduce "Narupa," a flexible, open-source, multiperson iMD-VR software framework which enables groups of researchers to simultaneously cohabit real-time simulation environments to interactively visualize and manipulate the dynamics of molecular structures with atomic-level precision. We outline several application domains where iMD-VR is facilitating research, communication, and creative approaches within the molecular sciences, including training machines to learn potential energy functions, biomolecular conformational sampling, protein-ligand binding, reaction discovery using "on-the-fly" quantum chemistry, and transport dynamics in materials. We touch on iMD-VR's various cognitive and perceptual affordances and outline how these provide research insight for molecular systems. By synergistically combining human spatial reasoning and design insight with computational automation, technologies such as iMD-VR have the potential to improve our ability to understand, engineer, and communicate microscopic dynamical behavior, offering the potential to usher in a new paradigm for engineering molecules and nano-architectures. [ABSTRACT FROM AUTHOR]

Published
2019
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94. Implicit solvent models fail to reproduce secondary structures of de novo designed peptides

Author

Lang, Eric J M, Baker, Emily G, Woolfson, Dek N, and Mulholland, Adrian J

Subjects
molecular dynamics simulation, computational protein design, de novo peptides, generalized Born, implicit solvent
Abstract

We test a range of standard implicit solvent models and protein forcefields for a set of 5 experimentally characterized, designed α-helical peptides. 65 combinations of forcefield and implicit solvent models are evaluated in >800 µs of molecular dynamics simulations. The data show that implicit solvent models generally fail to reproduce the experimentally observed secondary structure content, and none performs well for all 5 peptides. The results show that these models are not usefully predictive.

Published
2021

95. A multiscale approach to predict the binding mode of metallo beta-lactamase inhibitors: Binding mode prediction for IMP-1 inhibitors

Author

Gervasoni, Silvia, Spencer, James, Hinchliffe, Philip, Pedretti, Alessandro, Vairoletti, Franco, Mahler, Graciela, and Mulholland, Adrian J.

Subjects
Models, Molecular, Zinc, Catalytic Domain, beta-Lactamase Inhibitors, beta-Lactams, Article, beta-Lactamases, Anti-Bacterial Agents
Abstract

Antibiotic resistance is a major threat to global public health. β-lactamases, which catalyze breakdown of β-lactam antibiotics, are a principal cause. Metallo β-lactamases (MBLs) represent a particular challenge because they hydrolyze almost all β-lactams and to date no MBL inhibitor has been approved for clinical use. Molecular simulations can aid drug discovery, for example, predicting inhibitor complexes, but empirical molecular mechanics (MM) methods often perform poorly for metalloproteins. Here we present a multiscale approach to model thiol inhibitor binding to IMP-1, a clinically important MBL containing two catalytic zinc ions, and predict the binding mode of a 2-mercaptomethyl thiazolidine (MMTZ) inhibitor. Inhibitors were first docked into the IMP-1 active site, testing different docking programs and scoring functions on multiple crystal structures. Complexes were then subjected to molecular dynamics (MD) simulations and subsequently refined through QM/MM optimization with a density functional theory (DFT) method, B3LYP/6-31G(d), increasing the accuracy of the method with successive steps. This workflow was tested on two IMP-1:MMTZ complexes, for which it reproduced crystallographically observed binding, and applied to predict the binding mode of a third MMTZ inhibitor for which a complex structure was crystallographically intractable. We also tested a 12-6-4 nonbonded interaction model in MD simulations and optimization with a SCC-DFTB QM/MM approach. The results show the limitations of empirical models for treating these systems and indicate the need for higher level calculations, for example, DFT/MM, for reliable structural predictions. This study demonstrates a reliable computational pipeline that can be applied to inhibitor design for MBLs and other zinc-metalloenzyme systems.

Published
2021

98. Ligand-induced unfolding mechanism of an RNA G-quadruplex

Author

Haldar, Susanta, primary, Zhang, Yashu, additional, Xia, Ying, additional, Islam, Barira, additional, Liu, Sisi, additional, Gervasio, Francesco Luigi, additional, Mulholland, Adrian J, additional, Waller, Zoe, additional, Wei, Dengguo, additional, and Haider, Shozeb, additional

Published
2021
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