A topological data analytic approach for discovering biophysical signatures in protein dynamics.

Identifying structural differences among proteins can be a non-trivial task. When contrasting ensembles of protein structures obtained from molecular dynamics simulations, biologically-relevant features can be easily overshadowed by spurious fluctuations. Here, we present SINATRA Pro, a computational pipeline designed to robustly identify topological differences between two sets of protein structures. Algorithmically, SINATRA Pro works by first taking in the 3D atomic coordinates for each protein snapshot and summarizing them according to their underlying topology. Statistically significant topological features are then projected back onto a user-selected representative protein structure, thus facilitating the visual identification of biophysical signatures of different protein ensembles. We assess the ability of SINATRA Pro to detect minute conformational changes in five independent protein systems of varying complexities. In all test cases, SINATRA Pro identifies known structural features that have been validated by previous experimental and computational studies, as well as novel features that are also likely to be biologically-relevant according to the literature. These results highlight SINATRA Pro as a promising method for facilitating the non-trivial task of pattern recognition in trajectories resulting from molecular dynamics simulations, with substantially increased resolution.

Impact of pretreatments with ethanol and freezing on drying slice papaya: drying performance and kinetic of ultrasound-assisted extraction of phenolics compounds.

BACKGROUND: Pretreatments of drying can represent an alternative to minimize the negative aspect process on the dry samples. Thus, the influence of ethanol (ET) and freezing (FG) as drying pretreatments was analyzed for slices of papaya. The slices (5 mm) were submitted for drying kinetics (60 °C and 1.5 m s-1 ). Drying kinetics experimental data were fitted using Page's model and a diffusive model with boundary condition of types I and III. Also the thermophysical properties (thermal conductivity and specific heat) were determined and finally, the kinetics of ultrasound-assisted (40 kHz and 132 W) extraction of total phenolic compounds (TPCs) were realized. RESULTS: The combined method (ET + FG) was more efficient in reducing the drying time of papaya slices (48%) and the model 2 simulating the boundary condition of the third type (type III) showed the best fit to the experimental data. Effective diffusivity and convective coefficient were higher for ET + FG, where the maximum reduction in water content was 91% compared to fresh slices. The pretreatments did not influence the thermal conductivity, however, they were significant in the specific heat and in the extraction of TPCs, being higher in the time of 180 min. CONCLUSION: It was confirmed in the results presented that the combined pretreatment ET + FG is the most viable for drying papaya slices. Furthermore, it was found to be the most efficient in minimizing the loss of TPCs. Therefore, this pretreatment has great potential for application in the development of high value-added foods. © 2022 Society of Chemical Industry.

Predicting Relative Populations of Protein Conformations without a Physics Engine Using AlphaFold2.

This paper presents a novel approach for predicting the relative populations of protein conformations using AlphaFold 2, an AI-powered method that has revolutionized biology by enabling the accurate prediction of protein structures. While AlphaFold 2 has shown exceptional accuracy and speed, it is designed to predict proteins' single ground state conformations and is limited in its ability to predict fold switching and the effects of mutations on conformational landscapes. Here, we demonstrate how AlphaFold 2 can directly predict the relative populations of different conformations of proteins and even accurately predict changes in those populations induced by mutations by subsampling multiple sequence alignments. We tested our method against NMR experiments on two proteins with drastically different amounts of available sequence data, Abl1 kinase and the granulocyte-macrophage colony-stimulating factor, and predicted changes in their relative state populations with accuracies in excess of 80%. Our method offers a fast and cost-effective way to predict protein conformations and their relative populations at even single point mutation resolution, making it a useful tool for pharmacology, analyzing NMR data, and studying the effects of evolution.

Predicting Relative Populations of Protein Conformations without a Physics Engine Using AlphaFold 2.

This paper presents a novel approach for predicting the relative populations of protein conformations using AlphaFold 2, an AI-powered method that has revolutionized biology by enabling the accurate prediction of protein structures. While AlphaFold 2 has shown exceptional accuracy and speed, it is designed to predict proteins' ground state conformations and is limited in its ability to predict conformational landscapes. Here, we demonstrate how AlphaFold 2 can directly predict the relative populations of different protein conformations by subsampling multiple sequence alignments. We tested our method against NMR experiments on two proteins with drastically different amounts of available sequence data, Abl1 kinase and the granulocyte-macrophage colony-stimulating factor, and predicted changes in their relative state populations with more than 80% accuracy. Our subsampling approach worked best when used to qualitatively predict the effects of mutations or evolution on the conformational landscape and well-populated states of proteins. It thus offers a fast and cost-effective way to predict the relative populations of protein conformations at even single-point mutation resolution, making it a useful tool for pharmacology, NMR analysis, and evolution.

Assessment of the hypoglycemic effect of Bixin in alloxan-induced diabetic rats: in vivo and in silico studies.

The objectives of this study were to extract and purify Bixin from the seeds of Bixa orellana and to evaluate its hypoglycemic activity in vivo, as well as, to conduct an in silico study of selectivity on peroxisome proliferator-activated receptors via molecular docking and molecular dynamics simulations. Oral administration of Bixin (10 mg/kg) significantly reduced their glucose level that was alloxan-induced diabetic rats. Bixin showed in silico selectivity on peroxisome proliferator-activated receptors (PPARs), particularly by the peroxisome proliferator-activated receptor gamma (PPARγ), which supports the hypoglycemic activity of Bixin. From the results obtained, it can be inferred that Bixin presents hypoglycemic characteristics, which was confirmed by the results obtained from the in vivo and in silico tests. Bixin may act by other pathways to control blood glucose and thus it is possible that it presents a different toxicity profile than troglitazone, rosiglitazone and pioglitazone. However, more studies on the activity and toxicity of Bixin are needed to evaluate for further clinical use. Communicated by Ramaswamy H. Sarma.

Influence of co-cultures of Streptococcus thermophilus and probiotic lactobacilli on quality and antioxidant capacity parameters of lactose-free fermented dairy beverages containing Syzygium cumini (L.) Skeels pulp.

This study investigated the influence of probiotic lactobacilli in co-culture with Streptococcus thermophilus on composition, physicochemical parameters, microbial viability, sensory acceptability, antioxidant capacity and protein profile of lactose-free fermented dairy beverages with added whey, ß-galactosidase and jambolan (Syzygium cumini (L.) Skeels) pulp. Three beverages (T1, T2 and T3) were prepared with Streptococcus thermophilus TA-40 as starter culture. Lactobacillus rhamnosus LR32 and Lactobacillus casei BGP93 probiotic cultures were added into T2 and T3, respectively. The probiotic adjuvants slightly influenced the pH and titratable acidity of dairy beverages, with no influence on the proximate composition and on the sensory attributes. Samples presented fat and protein contents suitable to meet the requirements of "low-fat dairy beverages with non-dairy ingredients added" according to the Brazilian legislation, lactobacilli viability above 7 log CFU g-1 for both probiotics and total phenolic content around 40 mg GAE 100 g-1. Colour was the most evaluated sensory aspect (average scores close or higher than 8 in a scale from 0 to 10 for most of the sampling periods). The overall antioxidant capacity increased significantly following the addition of jambolan (p < 0.05), and significantly more during storage (p < 0.05), likely due to proteolysis verified in the electrophoresis gels, as a result of the metabolism of the lactic cultures. The dairy beverages studied are good options for functional foods due to their nutritional value, viability of probiotic lactobacilli, phenolic content, and antioxidant capacity, also serving lactose-intolerant people.

Oil from the fruits of Pterodon emarginatus Vog.: A traditional anti-inflammatory. Study combining in vivo and in silico.

ETHNOBOTANICAL RELEVANCE: The oil obtained from the fruits of Pterodon emarginatus Vog. (OPe) is used orally and topically, in traditional medicine for some purposes, such as acute and chronic inflammatory states as rheumatoid arthritis. MATERIALS AND METHODS: In this work, the anti-inflammatory activity of the OPe was demonstrated based on several animal models and presented an in silico study based on the 6α,7ß-dihydroxy-vouacapan-17ß-oic acid (DHVA) majority compound of the OPe to evaluate the interaction this compound, with cyclooxygenase-2 (COX-2) in 4COX (Mus musculus) and 5KIR (Homo sapiens) and molecular dynamics simulation. RESULTS: The OPe (498 mg/kg, p.o) significantly inhibited (p < 0.05, Student t-test) the primary and secondary reactions of arthritis by Freund's Complete Adjuvant (FCA) and in dermatitis induced by croton oil in mice, OPe inhibited peak of edema. In vascular permeability test in rats, the treatment with OPe was able to block the response to PGE2, serotonin, and bradykinin (p < 0.05, Student t-test). In the writhing test in mice, the OPe at doses of 498 and 980 mg/kg (p.o) produced inhibition of 73% and 92%, respectively, and was not significantly effective in the hot plate test. In the evaluation of the potency in relation to gastric injury (gastric ulcer induced by stress) and combined assay in the assessment of anti-inflammatory potency and gastric damage, it was observed that indomethacin (10 mg/kg, p.o.) inhibited carrageenan edema by 51% and produced a higher number of gastric lesions when compared to the group treated with OPe, where only areas of hyperemia were observed, without the occurrence of ulcerative lesion, and which inhibited the edema by 47%. In the in silico study, it was found that the DHVA is capable of binding to two organisms (4COX - Mus musculus and 5KIR - Homo sapiens), however, with higher binding affinity to the organism Homo sapiens. CONCLUSIONS: As expected, all tested ligands were capable of forming hydrogen interactions with residues at their respective binding sites, but the DHVA ligand was capable of creating slightly more hydrogen bonds when docked to either 4COX or 5KIR than the other tested ligands, thus demonstrating the participation of this compound in the anti-inflammatory and antialgic responses observed in the in vivo assays as a COX-2 inhibitor. Therefore, the results obtained support the traditional use of OPe for inflammatory and gastric problems.