Interactive molecular dynamics in virtual reality for accurate flexible protein-ligand docking

Simulating drug binding and unbinding is a challenge, as the rugged energy landscapes that separate bound and unbound states require extensive sampling that consumes significant computational resources. Here, we describe the use of interactive molecular dynamics in virtual reality (iMD-VR) as an accurate low-cost strategy for flexible protein-ligand docking. We outline an experimental protocol which enables expert iMD-VR users to guide ligands into and out of the binding pockets of trypsin, neuraminidase, and HIV-1 protease, and recreate their respective crystallographic protein-ligand binding poses within 5 - 10 minutes. Following a brief training phase, our studies shown that iMD-VR novices were able to generate unbinding and rebinding pathways on similar timescales as iMD-VR experts, with the majority able to recover binding poses within 2.15 Angstrom RMSD of the crystallographic binding pose. These results indicate that iMD-VR affords sufficient control for users to carry out the detailed atomic manipulations required to dock flexible ligands into dynamic enzyme active sites and recover crystallographic poses, offering an interesting new approach for simulating drug docking and generating binding hypotheses.Comment: PLOS ON

Exploring human-guided strategies for reaction network exploration:Interactive molecular dynamics in virtual reality as a tool for citizen scientists

The emerging fields of citizen science and gamification reformulate scientific problems as games or puzzles to be solved. Through engaging the wider non-scientific community, significant breakthroughs may be made by analyzing citizen-gathered data. In parallel, recent advances in virtual reality (VR) technology are increasingly being used within a scientific context and the burgeoning field of interactive molecular dynamics in VR (iMD-VR) allows users to interact with dynamical chemistry simulations in real time. Here, we demonstrate the utility of iMD-VR as a medium for gamification of chemistry research tasks. An iMD-VR "game" was designed to encourage users to explore the reactivity of a particular chemical system, and a cohort of 18 participants was recruited to playtest this game as part of a user study. The reaction game encouraged users to experiment with making chemical reactions between a propyne molecule and an OH radical, and "molecular snapshots" from each game session were then compiled and used to map out reaction pathways. The reaction network generated by users was compared to existing literature networks demonstrating that users in VR capture almost all the important reaction pathways. Further comparisons between humans and an algorithmic method for guiding molecular dynamics show that through using citizen science to explore these kinds of chemical problems, new approaches and strategies start to emerge.</p

TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection.

HIV infection induces phenotypic and functional changes to CD8+ T cells defined by the coordinated upregulation of a series of negative checkpoint receptors that eventually result in T cell exhaustion and failure to control viral replication. We report that effector CD8+ T cells during HIV infection in blood and SIV infection in lymphoid tissue exhibit higher levels of the negative checkpoint receptor TIGIT. Increased frequencies of TIGIT+ and TIGIT+ PD-1+ CD8+ T cells correlated with parameters of HIV and SIV disease progression. TIGIT remained elevated despite viral suppression in those with either pharmacological antiretroviral control or immunologically in elite controllers. HIV and SIV-specific CD8+ T cells were dysfunctional and expressed high levels of TIGIT and PD-1. Ex-vivo single or combinational antibody blockade of TIGIT and/or PD-L1 restored viral-specific CD8+ T cell effector responses. The frequency of TIGIT+ CD4+ T cells correlated with the CD4+ T cell total HIV DNA. These findings identify TIGIT as a novel marker of dysfunctional HIV-specific T cells and suggest TIGIT along with other checkpoint receptors may be novel curative HIV targets to reverse T cell exhaustion

Sampling molecular conformations and dynamics in a multiuser virtual reality framework

Copyright © 2018 The Authors, some rights reserved. We describe a framework for interactive molecular dynamics in a multiuser virtual reality (VR) environment, combining rigorous cloud-mounted atomistic physics simulations with commodity VR hardware, which we have made accessible to readers (see isci.itch.io/nsb-imd). It allows users to visualize and sample, with atomic-level precision, the structures and dynamics of complex molecular structures “on the fly” and to interact with other users in the same virtual environment. A series of controlled studies, in which participants were tasked with a range of molecular manipulation goals (threading methane through a nanotube, changing helical screw sense, and tying a protein knot), quantitatively demonstrate that users within the interactive VR environment can complete sophisticated molecular modeling tasks more quickly than they can using conventional interfaces, especially for molecular pathways and structural transitions whose conformational choreographies are intrinsically three-dimensional. This framework should accelerate progress in nanoscale molecular engineering areas including conformational mapping, drug development, synthetic biology, and catalyst design. More broadly, our findings highlight the potential of VR in scientific domains where three-dimensional dynamics matter, spanning research and education

Uterotonic agents for preventing postpartum haemorrhage:a network meta-analysis (Protocol)

Brathys e Trigynobrathys (88 e 59 representantes, respectivamente) são as duas maiores seções do gênero Hypericum que são distribuídos principalmente na América Central e América do Sul. Das mais de 100 espécies sul-americanas de Hypericum quase 65 são endêmicas dos Páramos, ecossistemas de alta altitude, caracterizados por uma vegetação composta principalmente de plantas de roseta gigantes, arbustos e gramíneas, nos quais Hypericum é um componente importante. Tendo em vista o escasso conhecimento da fitoquímica destas espécies de Hypericum, o presente estudo teve como objetivo estudar a composição fitoquímica e algumas bioatividades de seis espécies de Hypericum nativas do Peru (H. aciculare, H. andinum, H. brevistylum, H. decandrum, H. laricifolium e H. silenoides). O material vegetal, seco ao ar, das seis espécies (partes aéreas, caules, folhas e flores), e material vegetal subterrâneo de H. andinum (raízes e caules), foram moídas e extraídas por maceração à temperatura ambiente com n-hexano. Além disso, foram obtidos extrato etanólicos a partir de quatro espécies (H. andinum, H. brevistylum, H. laricifolium e H. silenoides). Os extratos n-hexano foram fracionados e as frações foram sometidas a processos cromatográficos obtendo-se cinco derivados de floroglucinol diméricos conhecidos, uliginosina A, uliginosina B, isouliginosina B, hiperbrasilol B e isohiperbrasilol B. Além disso, foram identificadas duas estruturas monoméricas e duas diméricas inéditas em H. andinum (raízes) e em H. laricifolium, andinina A, hiperlaricifolina A, laricifolina A e laricifolina B. Andinina A mostrou potencial atividade antidepressiva no teste de natação forçada. Do mesmo modo, a atividade antidepressiva dos extratos etanólicos foi avaliada. Estes quatro extratos apresentaram potencial atividade antidepressiva. As análises fitoquímicas por TLC, HPLC-DAD e UPLC-DAD/Q-TOF-MS revelaram que estes extratos são ricos em flavonoides, principalmente hiperosídeo. Os extratos n-hexano foram também analisados por um novo método de HPLC-DAD associado a LC-MS e UPLC-Q-TOF-MS . A presença de homólogos superiores M + 14 e regioisómeros foi determinada. A ocorrência natural destes cinco floroglucinois homólogos superiores M + 14 é descrita e a presença de outros compostos identificados pelo padrão de fragmentação MS é apresentada. Estes extratos e o seu principal componente foram capazes de inibir potencialmente a quimiotaxia induzida por LPS. Estes resultados sugerem que os extratos de espécies de Hypericum das seções Brathys e Trigynobrathys são fontes potenciais de novos anti-inflamatórios e antidepressivos.Brathys and Trigynobrathys (88 and 59 representatives, respectively) are the two largest sections of the genus Hypericum that are principally distributed in Central and South America. Of the more than 100 South American species of Hypericum almost 65 are endemic to the Páramos, high-altitude grassland ecosystems characterized by vegetation composed mainly of giant rosette plants, shrubs and grasses, in which Hypericum is a prominent component. In view of the scare knowledge on the phytochemistry of these Hypericum species, the present research aimed to study the phytochemical composition and some bioactivities of six Peruvian Hypericum species (H. aciculare, H. andinum, H. brevistylum, H. decandrum, H. laricifolium and H. silenoides). The air-dried aerial plant material of those six species (stems, leaves and flowers), and underground plant material of H. andinum (roots and stems), were ground and extracted by maceration at room temperature with n-hexane. Additionally crude ethanolic extracts were obtained from four species (H. andinum, H. brevistylum, H. laricifolium and H. silenoides). The n-hexane extracts were fractionated, and fractions were further processed by chromatographic procedures to yield five known dimeric acylphloroglucinol derivatives uliginosin A, uliginosin B, isouliginosin B, hyperbrasilol B and isohyperbrasilol B. In addition, two monomeric and two dimeric acylphloroglucinol structures were identified in H. andinum (roots extract) and H. laricifolium for the first time, andinin A, hyperlaricifolin A, laricifolin A and laricifolin B. Andinin A showed potential antidepressant-like activity in the forced swimming test. Similarly, the antidepressant-like activity of the crude ethanolic extracts was assessed. These four extracts possessed a potential antidepressant-like activity. The phytochemical analyses by TLC, HPLC-DAD and UPLCDAD/Q-TOF-MS revealed that the extracts were rich in flavonoids, principally hyperoside. The n-hexane extracts were also analyzed by a new HPLC-DAD fingerprint method associated with LC-MS and UPLC-Q-TOF-MS. The presence of M + 14 higher homologues and regioisomers could be distinguished. The natural occurrence of these five M + 14 higher homologues is described and the presence of other compounds identified by their MS fragmentation pattern is presented. These extracts and their main dimeric acylphloroglucinol component were able to potently inhibit the LPS-induced chemotaxis on rat PMN. These results suggest that extracts of Hypericum species from sections Brathys and Trigynobrathys are potential sources of new anti-inflammatory and antidepressant molecules

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

© 2019 Author(s). 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