ATOMDANCE: Kernel-based denoising and choreographic analysis for protein dynamic comparison.

Comparative methods in molecular evolution and structural biology rely heavily upon the site-wise analysis of DNA sequence and protein structure, both static forms of information. However, it is widely accepted that protein function results from nanoscale nonrandom machine-like motions induced by evolutionarily conserved molecular interactions. Comparisons of molecular dynamics (MD) simulations conducted between homologous sites representative of different functional or mutational states can potentially identify local effects on binding interaction and protein evolution. In addition, comparisons of different (i.e., nonhomologous) sites within MD simulations could be employed to identify functional shifts in local time-coordinated dynamics indicative of logic gating within proteins. However, comparative MD analysis is challenged by the large fraction of protein motion caused by random thermal noise in the surrounding solvent. Therefore, properly denoised MD comparisons could reveal functional sites involving these machine-like dynamics with good accuracy. Here, we introduce ATOMDANCE, a user-interfaced suite of comparative machine learning-based denoising tools designed for identifying functional sites and the patterns of coordinated motion they can create within MD simulations. ATOMDANCE-maxDemon4.0 employs Gaussian kernel functions to compute site-wise maximum mean discrepancy between learned features of motion, thereby assessing denoised differences in the nonrandom motions between functional or evolutionary states (e.g., ligand bound versus unbound, wild-type versus mutant). ATOMDANCE-maxDemon4.0 also employs maximum mean discrepancy to analyze potential random amino acid replacements allowing for a site-wise test of neutral versus nonneutral evolution on the divergence of dynamic function in protein homologs. Finally, ATOMDANCE-Choreograph2.0 employs mixed-model analysis of variance and graph network to detect regions where time-synchronized shifts in dynamics occur. Here, we demonstrate ATOMDANCE's utility for identifying key sites involved in dynamic responses during functional binding interactions involving DNA, small-molecule drugs, and virus-host recognition, as well as understanding shifts in global and local site coordination occurring during allosteric activation of a pathogenic protease.

Case Report: Shewanella Algae Pneumonia and Bacteremia in an Elderly Male Living at a Long-Term Care Facility.

Shewanella algae is a gram-negative, nonfermenting, oxidase-positive, motile bacillus that is ubiquitous in aquatic ecosystems. Human infections are rare and the immunocompromised are left most vulnerable. Risk factors for this infection include exposure to seawater, consumption of raw seafood, and underlying comorbid conditions such as hepatobiliary disease and chronic cutaneous ulcers. Previously documented cases of S. algae have involved near drownings, contaminated raw shellfish, or wound exposure to seawater, mud, sand, and sewage. This case study is unique in that it describes Shewanella bacteremia without any of these typical preceding exposures. We present a case of S. algae pneumonia and bacteremia in an elderly male patient living at a long-term care facility without any recent open water exposure.

Antioxidant and pro-oxidant mechanisms of (+) catechin in microsomal CYP2E1-dependent oxidative stress.

The objectives of this work were to evaluate the effects of catechin on cytochrome P450 2E1 (CYP2E1)-dependent oxidative stress. Microsomes co-expressing human CYP2E1 with NADPH cytochrome P450 reductase and cytochrome b5 were incubated with NADPH and DTPA at pH 7.0. Superoxide anion generation was specifically detected by spin-trapping with DEPMPO. Generation of the DEPMPO-OOH adduct was not observed in the absence of CYP2E1 and in the presence of superoxide dismutase (SOD) or catechin, while catalase was ineffective. Reactive oxygen species generation was detected with 1-hydroxy-3-carboxy-2,2,5,5-tetramethylpyrrolidine (CPH) by the EPR-detection of its oxidation product, 3-carboxy-proxyl radical (CP●). CP● generation was not observed in the absence of CYP2E1 and in the presence of SOD, while catalase was ineffective. In contrast, catechin increased CPH oxidation, an effect that was not observed in the absence of CYP2E1 or in the presence of SOD (but not catalase), and was not associated with an increase in oxygen consumption. Catechin also increased the non-specific oxidation of the probes CPH and hydroethidine by the superoxide anion-generating system xanthine plus xanthine oxidase. Catechin oxidized CPH in the presence of horseradish peroxidase plus hydrogen peroxide, a catechin radical-generating system. In conclusion, catechin exhibits both antioxidant (superoxide-scavenging) and pro-oxidant effects under CYP2E1-dependent oxidative stress.