SMOG@ctbp: simplified deployment of structure-based models in GROMACS

Molecular dynamics simulations with coarse-grained and/or simplified Hamiltonians are an effective means of capturing the functionally important long-time and large-length scale motions of proteins and RNAs. Structure-based Hamiltonians, simplified models developed from the energy landscape theory of protein folding, have become a standard tool for investigating biomolecular dynamics. SMOG@ctbp is an effort to simplify the use of structure-based models. The purpose of the web server is two fold. First, the web tool simplifies the process of implementing a well-characterized structure-based model on a state-of-the-art, open source, molecular dynamics package, GROMACS. Second, the tutorial-like format helps speed the learning curve of those unfamiliar with molecular dynamics. A web tool user is able to upload any multi-chain biomolecular system consisting of standard RNA, DNA and amino acids in PDB format and receive as output all files necessary to implement the model in GROMACS. Both Cα and all-atom versions of the model are available. SMOG@ctbp resides at http://smog.ucsd.edu

Industry-Informed Workshops to Develop Graduate Skill Sets in the Circular Economy Using Systems Thinking

Increasing demand for chemicals worldwide, depleting resources, consumer pressure, stricter legislation, and the rising cost of waste disposal are placing increasing pressure on chemical and related industries. For any organization to survive in the current arena of growing climate change laws and regulations, and increasing public influence, the issue of sustainability must be fundamental to the way it operates. A sustainable manufacturing approach will enable economic growth to be combined with environmental and social sustainability and will be realized via collaboration between a multidisciplinary community including chemists, biologists, engineers, environmental scientists, economists, experts in management, and policy makers. Hence, employees with new skills, knowledge, and experience are essential. To realize this approach, the design and development of a series of workshops encompassing systems thinking are presented here. After close consultation with industry, an annual program of interactive workshops has been designed for graduate students to go beyond examining the "greening" of chemical reactions, processes, and products, and instead embed a systems thinking approach to learning. The workshops provide a valuable insight into the issues surrounding sustainable manufacturing covering change management, commercialization, environmental impact, circular economy, legislation, and bioresources incorporating the conversion of waste into valuable products. The multidisciplinary course content incorporates industrial case studies, providing access to real business issues, and is delivered by experts from academic departments across campus and industry

Inter-relationship of plasma markers of oxidative stress and thyroid hormones in schizophrenics

<p>Abstract</p> <p>Background</p> <p>The relationship of oxidative stress to thyroid hormones has not been studied in the schizophrenics. The present study determined the status and interrelationship of plasma markers of oxidative stress, nitric oxide and thyroid hormones in thirty (17 males and 13 females) newly diagnosed patients with acute schizophrenia before initiation of chemotherapy. Twenty five (13 males and 12 females) mentally healthy individuals served as controls. Patients and controls with history of hard drugs (including alcohol and cigarette), pre-diagnosis medications (e.g. antiparkinsonian/antipsychotic drugs), chronic infections, liver disease and diabetes mellitus were excluded from the study. Plasma levels of total antioxidant potential (TAP), total plasma peroxides (TPP), nitric oxide (NO), malondialdehyde (MDA), thyroxine (T4), tri-iodothyronine (T3) and thyroid stimulating hormone (TSH) were determined in all participants using spectrophotometric and enzyme linked immunosorbent assay (ELISA) methods respectively. Oxidative stress index (OSI) was calculated as the percent ratio of total plasma peroxides and total antioxidant potential.</p> <p>Findings</p> <p>Significantly higher plasma levels of MDA (p < 0.01), TPP (p < 0.01), OSI (p < 0.01), T3 (p < 0.01) and T4 (p < 0.05) were observed in schizophrenics when compared with the controls. The mean levels of TAP, NO and TSH were significantly lower in schizophrenics (p < 0.01) when compared with the controls. The result shows that T3 values correlate significantly with MDA (p < 0.05) and TPP (p < 0.01) in schizophrenics.</p> <p>Conclusions</p> <p>Higher level of TPP may enhance thyroid hormogenesis in schizophrenics. Adjuvant antioxidant therapy may be a novel approach in the treatment of schizophrenic patients.</p

The Shadow Map: A General Contact Definition for Capturing the Dynamics of Biomolecular Folding and Function

Structure-based models (SBMs) are simplified models of the biomolecular dynamics that arise from funneled energy landscapes. We recently introduced an all-atom SBM that explicitly represents the atomic geometry of a biomolecule. While this initial study showed the robustness of the all-atom SBM Hamiltonian to changes in many of the energetic parameters, an important aspect, which has not been explored previously, is the definition of native interactions. In this study, we propose a general definition for generating atomically grained contact maps called “Shadow”. The Shadow algorithm initially considers all atoms within a cutoff distance and then, controlled by a screening parameter, discards the occluded contacts. We show that this choice of contact map is not only well behaved for protein folding, since it produces consistently cooperative folding behavior in SBMs but also desirable for exploring the dynamics of macromolecular assemblies since, it distributes energy similarly between RNAs and proteins despite their disparate internal packing. All-atom structure-based models employing Shadow contact maps provide a general framework for exploring the geometrical features of biomolecules, especially the connections between folding and function

Anisotropic Fluctuations in the Ribosome Determine tRNA Kinetics

The ribosome is a large ribonucleoprotein complex that is responsible for the production of proteins in all organisms. Accommodation is the process by which an incoming aminoacyl-tRNA (aa-tRNA) molecule binds the ribosomal A site, and its kinetics has been implicated in the accuracy of tRNA selection. In addition to rearrangements in the aa-tRNA molecule, the L11 stalk can undergo large-scale anisotropic motions during translation. To explore the potential impact of this protruding region on the rate of aa-tRNA accommodation, we used molecular dynamics simulations with a simplified model to evaluate the free energy as a function of aa-tRNA position. Specifically, these calculations describe the transition between A/T and elbow-accommodated (EA) configurations (∼20 Å displacement). We find that the free-energy barrier associated with elbow accommodation is proportional to the degree of mobility exhibited by the L11 stalk. That is, when L11 is more rigid, the free-energy barrier height is decreased. This effect arises from the ability of L11 to confine, and thereby destabilize, the A/T ensemble. In addition, when elongation factor Tu (EF-Tu) is present, the A/T ensemble is further destabilized in an L11-dependent manner. These results provide a framework that suggests how next-generation experiments may precisely control the dynamics of the ribosome

Reduced Model Captures Mg2+-RNA Interaction Free Energy of Riboswitches

The stability of RNA tertiary structures depends heavily on Mg(2+). The Mg(2+)-RNA interaction free energy that stabilizes an RNA structure can be computed experimentally through fluorescence-based assays that measure Γ2+, the number of excess Mg(2+) associated with an RNA molecule. Previous explicit-solvent simulations predict that the majority of excess Mg(2+) ions interact closely and strongly with the RNA, unlike monovalent ions such as K(+), suggesting that an explicit treatment of Mg(2+) is important for capturing RNA dynamics. Here we present a reduced model that accurately reproduces the thermodynamics of Mg(2+)-RNA interactions. This model is able to characterize long-timescale RNA dynamics coupled to Mg(2+) through the explicit representation of Mg(2+) ions. KCl is described by Debye-Hückel screening and a Manning condensation parameter, which represents condensed K(+) and models its competition with condensed Mg(2+). The model contains one fitted parameter, the number of condensed K(+) ions in the absence of Mg(2+). Values of Γ2+ computed from molecular dynamics simulations using the model show excellent agreement with both experimental data on the adenine riboswitch and previous explicit-solvent simulations of the SAM-I riboswitch. This agreement confirms the thermodynamic accuracy of the model via the direct relation of Γ2+ to the Mg(2+)-RNA interaction free energy, and provides further support for the predictions from explicit-solvent calculations. This reduced model will be useful for future studies of the interplay between Mg(2+) and RNA dynamics