A critical comparison of coarse-grained structure-based approaches and atomic models of protein folding.

Structure-based coarse-grained Go-like models have been used extensively in deciphering protein folding mechanisms because of their simplicity and tractability. Meanwhile, explicit-solvent molecular dynamics (MD) simulations with physics-based all-atom force fields have been applied successfully to simulate folding/unfolding transitions for several small, fast-folding proteins. To explore the degree to which coarse-grained Go-like models and their extensions to incorporate nonnative interactions are capable of producing folding processes similar to those in all-atom MD simulations, here we systematically compare the computed unfolded states, transition states, and transition paths obtained using coarse-grained models and all-atom explicit-solvent MD simulations. The conformations in the unfolded state in common Go models are more extended, and are thus more in line with experiment, than those from all-atom MD simulations. Nevertheless, the structural features of transition states obtained by the two types of models are largely similar. In contrast, the folding transition paths are significantly more sensitive to modeling details. In particular, when common Go-like models are augmented with nonnative interactions, the predicted dimensions of the unfolded conformations become similar to those computed using all-atom MD. With this connection, the large deviations of all-atom MD from simple diffusion theory are likely caused in part by the presence of significant nonnative effects in folding processes modelled by current atomic force fields. The ramifications of our findings to the application of coarse-grained modeling to more complex biomolecular systems are discussed.

Correction: A critical comparison of coarse-grained structure-based approaches and atomic models of protein folding.

Correction for 'A critical comparison of coarse-grained structure-based approaches and atomic models of protein folding' by Jie Hu et al., Phys. Chem. Chem. Phys., 2017, 19, 13629-13639.

The Folding of de Novo Designed Protein DS119 via Molecular Dynamics Simulations.

As they are not subjected to natural selection process, de novo designed proteins usually fold in a manner different from natural proteins. Recently, a de novo designed mini-protein DS119, with a ßαß motif and 36 amino acids, has folded unusually slowly in experiments, and transient dimers have been detected in the folding process. Here, by means of all-atom replica exchange molecular dynamics (REMD) simulations, several comparably stable intermediate states were observed on the folding free-energy landscape of DS119. Conventional molecular dynamics (CMD) simulations showed that when two unfolded DS119 proteins bound together, most binding sites of dimeric aggregates were located at the N-terminal segment, especially residues 5-10, which were supposed to form ß-sheet with its own C-terminal segment. Furthermore, a large percentage of individual proteins in the dimeric aggregates adopted conformations similar to those in the intermediate states observed in REMD simulations. These results indicate that, during the folding process, DS119 can easily become trapped in intermediate states. Then, with diffusion, a transient dimer would be formed and stabilized with the binding interface located at N-terminals. This means that it could not quickly fold to the native structure. The complicated folding manner of DS119 implies the important influence of natural selection on protein-folding kinetics, and more improvement should be achieved in rational protein design.

Long-term simulated microgravity alters gut microbiota and metabolome in mice.

Spaceflight and microgravity has a significant impact on the immune, central nervous, bone, and muscle support and cardiovascular systems. However, limited studies are available on the adverse effects of long-term microgravity on the intestinal microbiota, metabolism, and its relationships. In this study, a ground-based simulated microgravity (SMG) mouse model was established to evaluate the impact of long-term microgravity on gut microbiota and metabolome. After 8 weeks of SMG, alterations of the intestinal microbiota and metabolites were detected using 16S rRNA sequencing and untargeted metabolomics. Compared to the control, no significant differences in α-diversity were observed at weeks 2, 4 and 8. Nevertheless, there were clear differences in community structures at different time points. The phylum Verrucomicrobia significantly declined from 2 to 8 weeks of SMG, yet the relative abundance of Actinobacteria and Deferribacteres expanded remarkably at weeks 8. SMG decreased the genus of Allobaculum and increased Bacteroides significantly throughout the period of 8 weeks. Besides, Genus Akkermansia, Gracilibacter, Prevotella, Odoribacter, Rothia, Sporosarcina, Gracilibacter, Clostridium, and Mucispirillum were identified as biomarkers for SMG group. Desulfovibrio_c21_c20, Akkermansia_muciniphila, and Ruminococcus_gnavus dropped at week 2, which tend to recover at week 4, except for Akkermansia_muciniphila. Bacteroides_uniformis and Faecalibacterium_prausnitzii declined significantly, while Ruminococcus_flavefaciens and Mucispirillum_schaedleri elevated at week 8. Furthermore, intestinal metabolome analysis showed that 129 were upregulated and 146 metabolites were downregulated in SMG. Long-term SMG most affected steroid hormone biosynthesis, tryptophan, cysteine, methionine, arginine, proline metabolism, and histidine metabolism. Correlated analysis suggested that the potential beneficial taxa Allobaculum, Akkermansia, and Faecalibacterium were negatively associated with tryptophan, histidine, arginine, and proline metabolism, but positively with steroid hormone biosynthesis. Yet Bacteroides, Lachnospiraceae_Clostridium, Rothia, Bilophila, and Coprococcus were positively correlated with arginine, proline, tryptophan, and histidine metabolism, while negatively associated with steroid hormone biosynthesis. These results suggest that Long-term SMG altered the community of intestinal microbiota, and then further disturbed intestinal metabolites and metabolic pathways, which have great potential to help understand and provide clues for revealing the mechanisms of long-term SMG involved diseases.

[Collagen peptide partially restores immune function in mice under the condition of X-ray irradiation combined with simulated weightlessness].

Objective To investigate the effects of collagen peptides on the immune function of mice under the condition of X-ray irradiation combined with simulated weightlessness. Methods Mice were randomly divided into control group, modelling group and collagen peptide group. Mice in collagen peptide group were intraperitoneally injected with collagen peptide (600 mg/kg) once a day from the first day of the experiment, while mice in the other two groups were intraperitoneally injected with normal saline. On the fourth day of the experiment, mice in the modelling group and collagen peptide group were simultaneously exposed to X-ray irradiation (2 Gy) and hindlimb-unloaded simulated weightlessness by tail-suspension. On the 10th day of the experiment, the mice were terminated by cervical dislocation. Automated hematology analyzer was used to detect Leukocyte classification of peripheral blood. Splenic lymphocyte subsets, cell cycle and apoptosis of bone marrow cells were analyzed by flow cytometry. The expressions of 19 plasma cytokines were tested with liquid suspension chips. Results Compared with the control group, the modelling group had a significant reduction in the total number of white blood cells and lymphocytes in the peripheral blood, the total number of splenocyte and the number of T cells, CD4+ and CD8+ T cells, B cells, and natural killer (NK) cells in the spleen, an decrease in 18 cytokines in the plasma, and an increase in myelocyte apoptosis in mice of the modelling group. Compared with the modelling group, most immunological parameters had improved in the mice of the collagen peptide group except some cytokines. Conclusion Collagen peptides can effectively improve the immune function of mice under the condition of X-ray irradiation combined with simulated weightlessness.