Rational design of complex phenotype via network models.
Ontology highlight
ABSTRACT:
SUBMITTER: Gameiro M
PROVIDER: S-EPMC8354484 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND: Phenotypically similar diseases have been found to be caused by functionally related genes, suggesting a modular organization of the genetic landscape of human diseases that mirrors the modularity observed in biological interaction networks. Protein complexes, as molecular machines that integrate multiple gene products to perform biological functions, express the underlying modular organization of protein-protein interaction networks. As such, protein complexes can be useful for interrogating the networks of phenome and interactome to elucidate gene-phenotype associations of diseases. METHODOLOGY/PRINCIPAL FINDINGS: We proposed a technique called RWPCN (Random Walker on Protein Complex Network) for predicting and prioritizing disease genes. The basis of RWPCN is a protein complex network constructed using existing human protein complexes and protein interaction network. To prioritize candidate disease genes for the query disease phenotypes, we compute the associations between the protein complexes and the query phenotypes in their respective protein complex and phenotype networks. We tested RWPCN on predicting gene-phenotype associations using leave-one-out cross-validation; our method was observed to outperform existing approaches. We also applied RWPCN to predict novel disease genes for two representative diseases, namely, Breast Cancer and Diabetes. CONCLUSIONS/SIGNIFICANCE: Guilt-by-association prediction and prioritization of disease genes can be enhanced by fully exploiting the underlying modular organizations of both the disease phenome and the protein interactome. Our RWPCN uses a novel protein complex network as a basis for interrogating the human phenome-interactome network. As the protein complex network can capture the underlying modularity in the biological interaction networks better than simple protein interaction networks, RWPCN was found to be able to detect and prioritize disease genes better than traditional approaches that used only protein-phenotype associations.
| S-EPMC3143124 | biostudies-literature
Project description:Cas9, an RNA-guided DNA endonuclease found in clustered regularly interspaced short palindromic repeats (CRISPR) bacterial immune systems, is a versatile tool for genome editing, transcriptional regulation, and cellular imaging applications. Structures of Streptococcus pyogenes Cas9 alone or bound to single-guide RNA (sgRNA) and target DNA revealed a bilobed protein architecture that undergoes major conformational changes upon guide RNA and DNA binding. To investigate the molecular determinants and relevance of the interlobe rearrangement for target recognition and cleavage, we designed a split-Cas9 enzyme in which the nuclease lobe and α-helical lobe are expressed as separate polypeptides. Although the lobes do not interact on their own, the sgRNA recruits them into a ternary complex that recapitulates the activity of full-length Cas9 and catalyzes site-specific DNA cleavage. The use of a modified sgRNA abrogates split-Cas9 activity by preventing dimerization, allowing for the development of an inducible dimerization system. We propose that split-Cas9 can act as a highly regulatable platform for genome-engineering applications.
| S-EPMC4364227 | biostudies-literature
Project description:Rational design of drug-like small-molecule ligands based on structural information of proteins remains a significant challenge in chemical biology. In particular, designs targeting protein-protein interfaces have met little success given the dynamic nature of the protein surfaces. Herein, we utilized the structure of a small-molecule ligand in complex with Toll-like receptor 8 (TLR8) as a model system due to TLR8's clinical relevance. Overactivation of TLR8 has been suggested to play a prominent role in the pathogenesis of various autoimmune diseases; however, there are still few small-molecule antagonists available, and our rational designs led to the discovery of six exceptionally potent compounds with ?picomolar IC50 values. Two X-ray crystallographic structures validated the contacts within the binding pocket. A variety of biological evaluations in cultured cell lines, human peripheral blood mononuclear cells, and splenocytes from human TLR8-transgenic mice further demonstrated these TLR8 inhibitors' high efficacy, suggesting strong therapeutic potential against autoimmune disorders.
| S-EPMC6195466 | biostudies-literature
Project description:The field of complex self-assembly is moving toward the design of multiparticle structures consisting of thousands of distinct building blocks. To exploit the potential benefits of structures with such "addressable complexity," we need to understand the factors that optimize the yield and the kinetics of self-assembly. Here we use a simple theoretical method to explain the key features responsible for the unexpected success of DNA-brick experiments, which are currently the only demonstration of reliable self-assembly with such a large number of components. Simulations confirm that our theory accurately predicts the narrow temperature window in which error-free assembly can occur. Even more strikingly, our theory predicts that correct assembly of the complete structure may require a time-dependent experimental protocol. Furthermore, we predict that low coordination numbers result in nonclassical nucleation behavior, which we find to be essential for achieving optimal nucleation kinetics under mild growth conditions. We also show that, rather surprisingly, the use of heterogeneous bond energies improves the nucleation kinetics and in fact appears to be necessary for assembling certain intricate 3D structures. This observation makes it possible to sculpt nucleation pathways by tuning the distribution of interaction strengths. These insights not only suggest how to improve the design of structures based on DNA bricks, but also point the way toward the creation of a much wider class of chemical or colloidal structures with addressable complexity.
| S-EPMC4443370 | biostudies-literature
Project description:BackgroundStructural homology modeling supported by bioinformatics analysis plays a key role in uncovering new molecular interactions within gene regulatory networks. Here, we have applied this powerful approach to analyze the molecular interactions orchestrating death receptor signaling networks. In particular, we focused on the molecular mechanisms of CD95-mediated NF-κB activation and the role of c-FLIP/NEMO interaction in the induction of this pathway.ResultsTo this end, we have created the homology model of the c-FLIP/NEMO complex using the reported structure of the v-FLIP/NEMO complex, and rationally designed peptides targeting this complex. The designed peptides were based on the NEMO structure. Strikingly, the experimental in vitro validation demonstrated that the best inhibitory effects on CD95-mediated NF-κB activation are exhibited by the NEMO-derived peptides with the substitution D242Y of NEMO. Furthermore, we have assumed that the c-FLIP/NEMO complex is recruited to the DED filaments formed upon CD95 activation and validated this assumption in silico. Further insight into the function of c-FLIP/NEMO complex was provided by the analysis of evolutionary conservation of interacting regions which demonstrated that this interaction is common in distinct mammalian species.ConclusionsTaken together, using a combination of bioinformatics and experimental approaches we obtained new insights into CD95-mediated NF-κB activation, providing manifold possibilities for targeting the death receptor network.
| S-EPMC6900753 | biostudies-literature
Project description:Analysis of whole mouse muscle and inguinal lymph node gene expression signature induced after 24h by in-vivo intramuscularly administration of R848, SMIP-7.7, SMIP-7.8 and 4%DMSO controls. Analysis of whole mouse muscle and inguinal lymph node gene expression signature induced after 6h by in-vivo intramuscularly administration of R848 and SMIP-7.2 in 1% DMSO, and SMIP-7.10 and SMIP-7.10+alum in Buffer.
2015-11-02 | E-MTAB-2948 | biostudies-arrayexpress
Project description:The development of drugs to restore protein function has been a major advance facilitated by molecular medicine. Allosteric regulation, a phenomenon widely observed in nature, in which a molecule binds to control a distance active site, holds great promise for regulating proteins, yet how to rationally design such a molecule remains a mystery. Over the past few years, we and others have developed several techniques based on molecular dynamics (MD) simulations: MD-Markov state models to capture global conformational substates, and network theory approach utilizing the interaction energy within the protein to confer local allosteric control. We focus on the key case study of the p53 Y220C mutation restoration by PK11000, a compound experimentally shown to reactivate p53 native function in Y220C mutant present tumors. We gain insights into the mutation and allosteric reactivation of the protein, which we anticipate will be applicable to de novo design to engineer new compounds not only for this mutation, but in other macromolecular systems as well.
| S-EPMC8792916 | biostudies-literature
Project description:The phytohormone (+)-7-iso-jasmonoyl-L-isoleucine (JA-Ile) is a major regulator of developmental and stress responses in plants. The perception of JA-Ile involves the formation of a ternary complex with the F-box protein COI1 and a member of the JAZ family of co-repressors, which leads to JAZ degradation. Coronatine (COR) is a bacterial phytotoxin that functionally mimics JA-Ile and interacts with the co-receptor COI1-JAZ complex with higher affinity than JA-Ile. Based on the crystal structure of the co-receptor, we designed ligand derivatives that spatially impede the interaction of the co-receptor proteins and, therefore, should act as competitive antagonists of COR or JA-Ile. One derivative, Coronatine O-methyloxime (COR-MO), shows a strong activity preventing COI-JAZ interaction and the subsequent JAZ degradation. COR-MO efficiently reverts the effects of JA-Ile or COR treatments on JA-mediated responses, such as anthocyanin accumulation, root-growth inhibition and gene expression in Arabidopsis plants. Moreover, it potentiates plant resistance preventing the effect of bacterially produced COR during Pseudomonas syringae infections in different plant species. In addition to the utility of COR-MO for Plant Biology research, our results underscore its biotechnological and agronomical potential for a safer and sustainable agriculture. Two-condition experiment, Col-0 vs Col-0 plants treated 2h with Coronatine 0-methyloxime (COR-MO) and Col-0 plants treated 2h with Coronatine vs Col-0 plants treated 2h with Coronatine plus COR-MO. Biological replicates: 4 control and 4 treated replicates
2014-06-20 | E-GEOD-56027 | biostudies-arrayexpress
Project description:Efficient biosynthesis of the plant polyphenol pinosylvin, which has numerous applications in nutraceuticals and pharmaceuticals, is necessary to make biological production economically viable. To this end, an efficient Escherichia coli platform for pinosylvin production was developed via a rational modular design approach. Initially, different candidate pathway enzymes were screened to construct de novo pinosylvin pathway directly from D-glucose. A comparative analysis of pathway intermediate pools identified that this initial construct led to the intermediate cinnamic acid accumulation. The pinosylvin synthetic pathway was then divided into two new modules separated at cinnamic acid. Combinatorial optimization of transcriptional and translational levels of these two modules resulted in a 16-fold increase in pinosylvin titer. To further improve the concentration of the limiting precursor malonyl-CoA, the malonyl-CoA synthesis module based on clustered regularly interspaced short palindromic repeats interference was assembled and optimized with other two modules. The final pinosylvin titer was improved to 281 mg/L, which was the highest pinosylvin titer even directly from D-glucose without any additional precursor supplementation. The rational modular design approach described here could bolster our capabilities in synthetic biology for value-added chemical production.
| S-EPMC5431097 | biostudies-literature
Project description:Chromatographic characterization and parameterization studies targeting many solutes require the judicious choice of operating conditions to minimize analysis time without compromising the accuracy of the results. To minimize analysis time, solutes are often grouped into a small number of mixtures; however, this increases the risk of peak overlap. While multivariate curve resolution methods are often able to resolve analyte signals based on their spectral qualities, these methods require that the chromatographically overlapped compounds have dissimilar spectra. In this work, a strategy for grouping compounds into sample mixtures containing solutes with distinct spectral and, optionally, with distinct chromatographic properties, in order to ensure successful solute resolution either chromatographically or with curve resolution methods is proposed. We name this strategy rational design of mixtures (RDM). RDM utilizes multivariate selectivity as a metric for making decisions regarding group membership (i.e., whether to add a particular solute to a particular sample). A group of 97 solutes was used to demonstrate this strategy. Utilizing both estimated chromatographic properties and measured spectra to group these 97 analytes, only 12 groups were required to avoid a situation where two or more solutes in the same group could not be resolved either chromatographically (i.e., they have significantly different retention times) or spectrally (i.e., spectra are different enough to enable resolution by curve resolution methods). When only spectral properties were utilized (i.e., the chromatographic properties are unknown ahead of time) the number of groups required to avoid unresolvable overlaps increased to 20. The grouping strategy developed here will improve the time and instrument efficiency of studies that aim to obtain retention data for solutes as a function of operating conditions, whether for method development or determination of the chromatographic parameters of solutes of interest (e.g., k w ).
| S-EPMC7587020 | biostudies-literature