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

Good practice in food-related neuroimaging

The use of neuroimaging tools, especially functional magnetic resonance imaging, in nutritional research has increased substantially over the past 2 decades. Neuroimaging is a research tool with great potential impact on the field of nutrition, but to achieve that potential, appropriate use of techniques and interpretation of neuroimaging results is necessary. In this article, we present guidelines for good methodological practice in functional magnetic resonance imaging studies and flag specific limitations in the hope of helping researchers to make the most of neuroimaging tools and avoid potential pitfalls. We highlight specific considerations for food-related studies, such as how to adjust statistically for common confounders, like, for example, hunger state, menstrual phase, and BMI, as well as how to optimally match different types of food stimuli. Finally, we summarize current research needs and future directions, such as the use of prospective designs and more realistic paradigms for studying eating behavior

Modality-Dependent Impact of Hallucinations on Low-Frequency Fluctuations in Schizophrenia

Prior resting-state functional magnetic resonance imaging (fMRI) analyses have identified patterns of functional connectivity associated with hallucinations in schizophrenia (Sz). In this study, we performed an analysis of the mean amplitude of low-frequency fluctuations (ALFF) to compare resting state spontaneous low-frequency fluctuations in patients with Sz who report experiencing hallucinations impacting different sensory modalities. By exploring dynamics across 2 low-frequency passbands (slow-4 and slow-5), we assessed the impact of hallucination modality and frequency range on spatial ALFF variation. Drawing from a sample of Sz and healthy controls studied as part of the Functional Imaging Biomedical Informatics Research Network (FBIRN), we replicated prior findings showing that patients with Sz have decreased ALFF in the posterior brain in comparison to controls. Remarkably, we found that patients that endorsed visual hallucinations did not show this pattern of reduced ALFF in the back of the brain. These patients also had elevated ALFF in the left hippocampus in comparison to patients that endorsed auditory (but not visual) hallucinations. Moreover, left hippocampal ALFF across all the cases was related to reported hallucination severity in both the auditory and visual domains, and not overall positive symptoms. This supports the hypothesis that dynamic changes in the ALFF in the hippocampus underlie severity of hallucinations that impact different sensory modalities

Five Negative Symptom Domains Are Differentially Associated With Resting State Amplitude of Low Frequency Fluctuations in Schizophrenia

This study examined associations between resting-state amplitude of low frequency fluctuations (ALFF) and negative symptoms represented by total scores, second-order dimension (motivation and pleasure, expressivity), and first-order domain (anhedonia, avolition, asociality, alogia, blunted affect) factor scores in schizophrenia (n = 57). Total negative symptom scores showed positive associations with ALFF in temporal and frontal brain regions. Negative symptom domain scores showed predominantly stronger associations with regional ALFF compared to total scores, suggesting domain scores may better map to neural signatures than total scores. Improving our understanding of the neuropathology underlying negative symptoms may aid in addressing this unmet therapeutic need in schizophrenia

Cerebral Blood Flow and Cardiovascular Risk Effects on Resting Brain Regional Homogeneity

Regional homogeneity (ReHo) is a measure of local functional brain connectivity that has been reported to be altered in a wide range of neuropsychiatric disorders. Computed from brain resting-state functional MRI time series, ReHo is also sensitive to fluctuations in cerebral blood flow (CBF) that in turn may be influenced by cerebrovascular health. We accessed cerebrovascular health with Framingham cardiovascular risk score (FCVRS). We hypothesize that ReHo signal may be influenced by regional CBF; and that these associations can be summarized as FCVRS→CBF→ReHo. We used three independent samples to test this hypothesis. A test-retest sample of N = 30 healthy volunteers was used for test-retest evaluation of CBF effects on ReHo. Amish Connectome Project (ACP) sample (N = 204, healthy individuals) was used to evaluate association between FCVRS and ReHo and testing if the association diminishes given CBF. The UKBB sample (N = 6,285, healthy participants) was used to replicate the effects of FCVRS on ReHo. We observed strong CBF→ReHo links (p\u3c2.5 × 10−3) using a three-point longitudinal sample. In ACP sample, marginal and partial correlations analyses demonstrated that both CBF and FCVRS were significantly correlated with the whole-brain average (p\u3c10−6) and regional ReHo values, with the strongest correlations observed in frontal, parietal, and temporal areas. Yet, the association between ReHo and FCVRS became insignificant once the effect of CBF was accounted for. In contrast, CBF→ReHo remained significantly linked after adjusting for FCVRS and demographic covariates (p\u3c10−6). Analysis in N = 6,285 replicated the FCVRS→ReHo effect (p = 2.7 × 10−27). In summary, ReHo alterations in health and neuropsychiatric illnesses may be partially driven by region-specific variability in CBF, which is, in turn, influenced by cardiovascular factors

Measurement of the Lifetime Difference Between B_s Mass Eigenstates

We present measurements of the lifetimes and polarization amplitudes for B_s --> J/psi phi and B_d --> J/psi K*0 decays. Lifetimes of the heavy (H) and light (L) mass eigenstates in the B_s system are separately measured for the first time by determining the relative contributions of amplitudes with definite CP as a function of the decay time. Using 203 +/- 15 B_s decays, we obtain tau_L = (1.05 +{0.16}/-{0.13} +/- 0.02) ps and tau_H = (2.07 +{0.58}/-{0.46} +/- 0.03) ps. Expressed in terms of the difference DeltaGamma_s and average Gamma_s, of the decay rates of the two eigenstates, the results are DeltaGamma_s/Gamma_s = (65 +{25}/-{33} +/- 1)%, and DeltaGamma_s = (0.47 +{0.19}/-{0.24} +/- 0.01) inverse ps.Comment: 8 pages, 3 figures, 2 tables; as published in Physical Review Letters on 16 March 2005; revisions are for length and typesetting only, no changes in results or conclusion

HIVToolbox, an Integrated Web Application for Investigating HIV

Many bioinformatic databases and applications focus on a limited domain of knowledge federating links to information in other databases. This segregated data structure likely limits our ability to investigate and understand complex biological systems. To facilitate research, therefore, we have built HIVToolbox, which integrates much of the knowledge about HIV proteins and allows virologists and structural biologists to access sequence, structure, and functional relationships in an intuitive web application. HIV-1 integrase protein was used as a case study to show the utility of this application. We show how data integration facilitates identification of new questions and hypotheses much more rapid and convenient than current approaches using isolated repositories. Several new hypotheses for integrase were created as an example, and we experimentally confirmed a predicted CK2 phosphorylation site. Weblink: [http://hivtoolbox.bio-toolkit.com