Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock

<p>Abstract</p> <p>Background</p> <p>Molecular docking methods are commonly used for predicting binding modes and energies of ligands to proteins. For accurate complex geometry and binding energy estimation, an appropriate method for calculating partial charges is essential. AutoDockTools software, the interface for preparing input files for one of the most widely used docking programs AutoDock 4, utilizes the Gasteiger partial charge calculation method for both protein and ligand charge calculation. However, it has already been shown that more accurate partial charge calculation - and as a consequence, more accurate docking- can be achieved by using quantum chemical methods. For docking calculations quantum chemical partial charge calculation as a routine was only used for ligands so far. The newly developed Mozyme function of MOPAC2009 allows fast partial charge calculation of proteins by quantum mechanical semi-empirical methods. Thus, in the current study, the effect of semi-empirical quantum-mechanical partial charge calculation on docking accuracy could be investigated.</p> <p>Results</p> <p>The docking accuracy of AutoDock 4 using the original AutoDock scoring function was investigated on a set of 53 protein ligand complexes using Gasteiger and PM6 partial charge calculation methods. This has enabled us to compare the effect of the partial charge calculation method on docking accuracy utilizing AutoDock 4 software. Our results showed that the docking accuracy in regard to complex geometry (docking result defined as accurate when the RMSD of the first rank docking result complex is within 2 Å of the experimentally determined X-ray structure) significantly increased when partial charges of the ligands and proteins were calculated with the semi-empirical PM6 method.</p> <p>Out of the 53 complexes analyzed in the course of our study, the geometry of 42 complexes were accurately calculated using PM6 partial charges, while the use of Gasteiger charges resulted in only 28 accurate geometries. The binding affinity estimation was not influenced by the partial charge calculation method - for more accurate binding affinity prediction development of a new scoring function for AutoDock is needed.</p> <p>Conclusion</p> <p>Our results demonstrate that the accuracy of determination of complex geometry using AutoDock 4 for docking calculation greatly increases with the use of quantum chemical partial charge calculation on both the ligands and proteins.</p

‘ASMR’ autobiographies and the (life-)writing of digital subjectivity

For years now, a growing online subculture has been exchanging videos designed to induce ‘autonomous sensory meridian response’ (ASMR), a mysterious, blissfully relaxing tingling sensation held to alleviate anxiety, pain, insomnia and depression. Emerging from online health forums, ASMR culture today centres on YouTube, where ‘ASMRtists’ have used the feedback mechanisms built into social media platforms to refine a repertoire of ‘trigger’ techniques. Exemplifying a wider trend for using ‘ambient media’ as mood modulators and task facilitators (Roquet, 2016 Ambient Media: Japanese Atmospheres of Self. London: University of Minnesota Press.), ASMR culture’s use of the word ‘trigger’ is telling, gesturing towards what Halberstam ((2014) You Are Triggering Me! The Neo-Liberal Rhetoric of Harm, Danger and Trauma. Bully Bloggers. Available at: https://bullybloggers.wordpress.com/2014/07/05/you-are-triggering-me-the-neo-liberal-rhetoric-of-harm-danger-and-trauma/ (accessed 8 August 2018)) sees as a shift away from the Freudian notion of ‘memory as a palimpsest’ towards one of memory as ‘a live wire sitting in the psyche waiting for a spark’, whereby digital subjects become black-boxed nodes in a cybernetic circuit. This shift has serious implications for the humanities and is particularly resonant for scholars of life-writing. As McNeill ((2012) There is no “I” in network: Social networks sites and posthuman auto/biography. Biography 35(1): 65–82.) argues, digital technologies ‘complicate[] definitions of the self and its boundaries, both dismantling and sustaining the humanist subject in practices of personal narrative’ (p. 65). The resulting friction is highlighted in ‘ASMR autobiographies’: texts narrating the author’s experiences of ASMR and their discovery of online ASMR communities. Echoing familiar auto/biographical forms, from medical case histories and coming out narratives to tales of religious conversion, these texts show that the models of subjectivity we have inherited from Enlightenment philosophy, religion, psychology and Romantic literature retain some cultural purchase. But they also suggest digital media are fostering new understandings of personhood informed by cybernetics, evolutionary psychology, behaviourism and neuroscience. Focusing on works by Andrew MacMuiris, Andrea Seigel and Jon Kersey while also addressing a range of other texts, this article asks what ASMR autobiographies can tell us about digital subjectivity

The Staphylococcus aureus Response to Unsaturated Long Chain Free Fatty Acids: Survival Mechanisms and Virulence Implications

Staphylococcus aureus is an important human commensal and opportunistic pathogen responsible for a wide range of infections. Long chain unsaturated free fatty acids represent a barrier to colonisation and infection by S. aureus and act as an antimicrobial component of the innate immune system where they are found on epithelial surfaces and in abscesses. Despite many contradictory reports, the precise anti-staphylococcal mode of action of free fatty acids remains undetermined. In this study, transcriptional (microarrays and qRT-PCR) and translational (proteomics) analyses were applied to ascertain the response of S. aureus to a range of free fatty acids. An increase in expression of the σB and CtsR stress response regulons was observed. This included increased expression of genes associated with staphyloxanthin synthesis, which has been linked to membrane stabilisation. Similarly, up-regulation of genes involved in capsule formation was recorded as were significant changes in the expression of genes associated with peptidoglycan synthesis and regulation. Overall, alterations were recorded predominantly in pathways involved in cellular energetics. In addition, sensitivity to linoleic acid of a range of defined (sigB, arcA, sasF, sarA, agr, crtM) and transposon-derived mutants (vraE, SAR2632) was determined. Taken together, these data indicate a common mode of action for long chain unsaturated fatty acids that involves disruption of the cell membrane, leading to interference with energy production within the bacterial cell. Contrary to data reported for other strains, the clinically important EMRSA-16 strain MRSA252 used in this study showed an increase in expression of the important virulence regulator RNAIII following all of the treatment conditions tested. An adaptive response by S. aureus of reducing cell surface hydrophobicity was also observed. Two fatty acid sensitive mutants created during this study were also shown to diplay altered pathogenesis as assessed by a murine arthritis model. Differences in the prevalence and clinical importance of S. aureus strains might partly be explained by their responses to antimicrobial fatty acids

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

On the threshold for wave breaking of two-dimensional deep water wave groups in the absence and presence of wind

The threshold for the onset of breaking proposed by Barthelemy et al. (arXiv:1508.06002v1, 2015) has been investigated in the laboratory for unidirectional wave groups in deep water and extended to include different classes of wave groups and moderate wind forcing. Thermal image velocimetry was used to compare measurements of the wave crest point (maximum elevation and also the point of maximum) surface water particle velocity (Us) with the wave crest point speed (C) determined by an array of closely spaced wave gauges. The crest point surface energy flux ratio Bx = Us/C that distinguishes maximum recurrence from marginal breaking was found to be 0.840 ± 0.016. Increasing wind forcing from zero to Uλ/r/C0 = 1.42 systematically increased this threshold by 2 %. Increasing the spectral bandwidth (decreasing the Benjamin-Feir index from 0.39 to 0.31) systematically reduced the threshold by 1.5 %