Quantitative Biology

The spike glycoprotein of the SARS-CoV-2 virus, which causes COVID-19, has attracted attention for its vaccine potential and binding capacity to host cell surface receptors. Much of this research focus has centered on the ectodomain of the spike protein. The ectodomain is anchored to a transmembrane region, followed by a cytoplasmic tail. Here we report a distant sequence similarity between the cysteine-rich cytoplasmic tail of the coronavirus spike protein and the hepcidin protein that is found in humans and other vertebrates. Hepcidin is thought to be the key regulator of iron metabolism in humans. An implication of this preliminary observation is to suggest a potential route of investigation in the coronavirus research field making use of an already-established literature on the interplay of local and systemic iron regulation, cytokine-mediated inflammatory processes, respiratory infections and the hepcidin protein. The question of possible homology and an evolutionary connection between the viral spike protein and hepcidin is not assessed in this report, but some scenarios for its study are discussed.

Experiments measuring currents through single protein channels show unstable currents, a phenomena called the gating of a single channel. Channels switch between an 'open' state with a well defined single amplitude of current and 'closed' states with nearly zero current. The existing mean-field theory of ion channels focuses almost solely on the open state. The physical modeling of the dynamical features of ion channels is still in its infancy, and does not describe the transitions between open and closed states, nor the distribution of the duration times of open states. One hypothesis is that gating corresponds to noise-induced fast transitions between multiple steady (equilibrium) states of the underlying system. In this work, we aim to test this hypothesis. Particularly, our study focuses on the (high order) steric Poisson-Nernst-Planck-Cahn-Hilliard model since it has been successful in predicting permeability and selectivity of ionic channels in their open state, and since it gives rise to multiple steady states. We show that this system gives rise to a gating-like behavior, but that important features of this switching behavior are different from the defining features of gating in biological systems. Furthermore, we show that noise prohibits switching in the system of study. The above phenomena are expected to occur in other PNP-type models, strongly suggesting that one has to go beyond over-damped (gradient flow) Nernst-Planck type dynamics to explain the spontaneous gating of single channels.

The present Health Crisis tests the response of modern science and medicine to finding treatment for a new COVID-19 disease. The presentation on the world stage of antivirals such as remdesivir, obeys to the continuous investigation of biologically active molecules with multiple theoretical, computational and experimental tools. Diseases such as COVID:19 remind us that research into active ingredients for therapeutic purposes should cover all available sources, such as plants. In the present work, in silico tools, specifically docking study, were used to evaluate the binding and inhibition capacity of an antiviral such as remdesivir on the NSP-12 protein of SARS-CoV, a polymerase that is key in the replication of the SARS-COV virus. The results are then compared with a docking analysis of two natural products (Alpha-Bisabolol and betalain) with SARS-CoV protein, in order to find more candidates for COVID-19 virus replication inhibitors. in addition to increasing studies that help explain the specific mechanisms of the SARs-CoV-2 virus, remembering that we will have to live with the virus for an indefinite time from now on. Finally, natural products such as betalains may have inhibitory effects of a small order but in conjunction with other synergistic active ingredients they may increase their inhibition effect on NSP-12 protein of SARS-CoV.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the strain of coronavirus that causes coronavirus disease 2019 (COVID-19), the respiratory illness responsible for the COVID-19 pandemic. Currently there is no known vaccine or specific antiviral treatment for COVID-19 and so, there is an urgent need for expedite discovery of new therapeutics to combat the disease until a vaccine will be available worldwide. Drug repurposing is a strategy for identifying new uses for approved drugs that has the advantage (over conventional approaches that attempt to develop a drug from scratch) that time frame of the overall process can be significantly reduced because of the few number of clinical trial required. In this work, a virtual screening of FDA-approved drugs was performed for repositioning as potential inhibitors of the main protease Mpro of SARS-CoV-2. As a result of this study, 12 drugs are proposed as candidates for inhibitors of the Mpro enzyme. Some of the selected compounds are antiviral drugs that are already being tested in COVID-19 clinical trials (i.e. ribavirin) or are used to alleviate symptoms of the disease (i.e. codeine). Surprisingly, the most promising candidate is the naturally occurring broad spectrum antibiotic oxytetracycline. This compound has largely outperformed the remaining selected candidates along all filtering steps of our virtual screening protocol. If the activity of any of these drugs is experimentally corroborated, they could be used directly in clinical trials without the need for pre-clinical testing or safety evaluation since they are already used as drugs for other diseases.

Understanding E3 ligase and target substrate interactions are important for cell biology and therapeutic development. However, experimental identification of E3 target relationships is not an easy task due to the labor-intensive nature of the experiments. In this article, a sequence-based E3-target prediction model is proposed for the first time. The proposed framework utilizes composition of k-spaced amino acid pairs (CKSAAP) to learn the relationship between E3 ligases and their target protein. A class separable latent space encoding scheme is also devised that provides a compressed representation of feature space. A thorough ablation study is performed to identify an optimal gap size for CKSAAP and the number of latent variables that can represent the E3-target relationship successfully. The proposed scheme is evaluated on an independent dataset for a variety of standard quantitative measures. In particular, it achieves an average accuracy of 70.63% on an independent dataset. The source code and datasets used in the study are available at the author's GitHub page (this https URL).

In this paper, we propose a novel approach for manifold learning that combines the Earthmover's distance (EMD) with the diffusion maps method for dimensionality reduction. We demonstrate the potential benefits of this approach for learning shape spaces of proteins and other flexible macromolecules using a simulated dataset of 3-D density maps that mimic the non-uniform rotary motion of ATP synthase. Our results show that EMD-based diffusion maps require far fewer samples to recover the intrinsic geometry than the standard diffusion maps algorithm that is based on the Euclidean distance. To reduce the computational burden of calculating the EMD for all volume pairs, we employ a wavelet-based approximation to the EMD which reduces the computation of the pairwise EMDs to a computation of pairwise weighted- ℓ 1 distances between wavelet coefficient vectors.

The total phenols and flavonoids content of different polar solvent extracts from Aurea Helianthus flowers, and their antioxidant activity were determined. The ethanol extract of Aurea Helianthus flowers were suspended in water and fractionated using different polar solvents; hexane, chloroform, ethyl acetate, butanol and water. The parameters of each extract mentioned above were determined using Floin-ciocalteu reagent(FCR) method, AlCl3 colorimetry method, ferric reducing ability of plasma(FRAP) assay, total antioxidant activity(TAA) assay and DPPH radical scavenging assay. The highest total phenols content(516.21 mg GAE/g) and flavonoids content(326.06 mg QCE/g) were obtained in ethyl acetate extract, the correlation between TPC and TFC assay was founded to be 0.967. All polar solvent extracts of Aurea Helianthus flowers showed significant antioxidant effects, the hightest inhibition was obtained in ethyl acetate and choroform extracts and the lowest inhibition in the water extract. There is a good correlation of total phenols and flavonoids content with antioxidant activity. This work indicated that the polar solvent extracts of Aurea Helianthus flowers contain high phenols and flavonoids content and exhibited antioxidant activities in vitro, therefore, could be candidates for use as natural antioxidant.

Cotranslational folding depends on the folding speed and stability of the nascent protein. It remains difficult, however, to predict which proteins cotranslationally fold. Here, we simulate evolution of model proteins to investigate how native structure influences evolution of cotranslational folding. We developed a model that connects protein folding during and after translation to cellular fitness. Model proteins evolved improved folding speed and stability, with proteins adopting one of two strategies for folding quickly. Low contact order proteins evolve to fold cotranslationally. Such proteins adopt native conformations early on during the translation process, with each subsequently translated residue establishing additional native contacts. On the other hand, high contact order proteins tend not to be stable in their native conformations until the full chain is nearly extruded. We also simulated evolution of slowly translating codons, finding that slower translation speeds at certain positions enhances cotranslational folding. Finally, we investigated real protein structures using a previously published dataset that identified evolutionarily conserved rare codons in E. coli genes and associated such codons with cotranslational folding intermediates. We found that protein substructures preceding conserved rare codons tend to have lower contact orders, in line with our finding that lower contact order proteins are more likely to fold cotranslationally. Our work shows how evolutionary selection pressure can cause proteins with local contact topologies to evolve cotranslational folding.

An active loop-extrusion mechanism is regarded as the main out--of--equilibrium mechanism responsible for the structuring of megabase-sized domains in chromosomes. We developed a model to study the dynamics of the chromosome fibre by solving the kinetic equations associated with the motion of the extruder. By averaging out the position of the extruder along the chain, we build an effective equilibrium model capable of reproducing experimental contact maps based solely on the positions of extrusion--blocking proteins. We assessed the quality of the effective model using numerical simulations of chromosomal segments and comparing the results with explicit-extruder models and experimental data.

Hsp70 molecular chaperones are abundant ATP-dependent nanomachines that actively reshape non-native, misfolded proteins and assist a wide variety of essential cellular processes. Here we combine complementary computational/theoretical approaches to elucidate the structural and thermodynamic details of the chaperone-induced expansion of a substrate protein, with a particular emphasis on the critical role played by ATP hydrolysis. We first determine the conformational free-energy cost of the substrate expansion due to the binding of multiple chaperones using coarse-grained molecular simulations. We then exploit this result to implement a non-equilibrium rate model which estimates the degree of expansion as a function of the free energy provided by ATP hydrolysis. Our results are in quantitative agreement with recent single-molecule FRET experiments and highlight the stark non-equilibrium nature of the process, showing that Hsp70s are optimized to convert effectively chemical energy into mechanical work close to physiological conditions.