Post-translational processing leads to conformational changes in protein structure that modulate molecular functions and change the signature of metabolic transformations and immune responses. Some ...post-translational modifications (PTMs), such as phosphorylation and acetylation, are strongly related to oncogenic processes and malignancy. This study investigated a PTM pattern in patients with gender-specific ovarian or breast cancer. Proteomic profiling and analysis of cancer-specific PTM patterns were performed using high-resolution UPLC-MS/MS. Structural analysis, topology, and stability of PTMs associated with sex-specific cancers were analyzed using molecular dynamics modeling. We identified highly specific PTMs, of which 12 modified peptides from eight distinct proteins derived from patients with ovarian cancer and 6 peptides of three proteins favored patients from the group with breast cancer. We found that all defined PTMs were localized in the compact and stable structural motifs exposed outside the solvent environment. PTMs increase the solvent-accessible surface area of the modified moiety and its active environment. The observed conformational fluctuations are still inadequate to activate the structural degradation and enhance protein elimination/clearance; however, it is sufficient for the significant modulation of protein activity.
The theory of fluids is used to modify the integral equations of the reference interaction site model (RISM) approximation. Its applicability to the study of biomolecules solvation is evaluated. ...Unlike traditional RISM applications, the new integral equation contains an intramolecular correlation matrix that only needs to be calculated once. This allows us to bypass the effort of repeatedly solving RISM equations and the time-consuming averaging of values obtained for each time point of a molecular trajectory. The new approach allows for the assessment of the conformational transience of dissolved molecules while taking into account the effects of solvation. The free energy of oxytocin, which is a peptide hormone, as well as self-assembled ionic peptide complexes calculated using both the traditional RISM and the new RISM with average matrix (RISM-AM) approach are estimated. The free energy of oxytocin calculated using RISM-AM shows that the statistical error does not exceed the error obtained by standard averaging of solutions in the RISM equation. Despite the somewhat ambiguous results obtained for ionic peptide self-assembly using RISM-AM with Lennard–Jones repulsion correction, this method can still be considered applicable for fast molecular dynamics analysis. Since the required computational power can be reduced by at least two orders of magnitude, the medium-matrix RISM is indeed a highly applicable tool for studying macromolecular conformations as well as corresponding solvation effects.
New advances in protein post-translational modifications (PTMs) have revealed a complex layer of regulatory mechanisms through which PTMs control cell signaling and metabolic pathways, contributing ...to the diverse metabolic phenotypes found in cancer. Using conformational templates and the three-dimensional (3D) environment investigation of proteins in patients with colorectal cancer, it was demonstrated that most PTMs (phosphorylation, acetylation, and ubiquitination) are localized in the supersecondary structures (helical pairs). We showed that such helical pairs are represented on the outer surface of protein molecules and characterized by a largely accessible area for the surrounding solvent. Most promising and meaningful modifications were observed on the surface of vitamin D-binding protein (VDBP), complement C4-A (CO4A), X-ray repair cross-complementing protein 6 (XRCC6), Plasma protease C1 inhibitor (IC1), and albumin (ALBU), which are related to colorectal cancer developing. Based on the presented data, we propose the impact of the observed modifications in immune response, inflammatory reaction, regulation of cell migration, and promotion of tumor growth. Here, we suggest a computational approach in which high-throughput analysis for identification and characterization of PTM signature, associated with cancer metabolic reprograming, can be improved to prognostic value and bring a new strategy to the targeted therapy.
A closed chain of oscillators can be considered a model for ring-shaped ecosystems, such as atolls or the coastal zones of inland reservoirs. We use the logistic map, which is often referred to as an ...archetypical example of how complex dynamics can arise from very simple nonlinear equations, as a model for a separate oscillator in the chain. We present an original algorithm that allows us to find solutions to the spatiotemporal logistic equation quite efficiently or to state with certainty that there are no such solutions. Based on the Shannon formula, we propose formulas for estimating the spatial and temporal entropy, which allow us to classify our solutions as regular or irregular. We show that regular solutions can occur within the Malthus parameter region that corresponds to the irregular dynamics of a solitary logistic map.
Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment worldwide. The development of AMD is associated with inflammation, oxidative stress, and progressive ...proteostasis imbalance, in the regulation of which c-Jun N-terminal kinases (JNK) play a crucial role. JNK inhibition is discussed as an alternative way for prevention and treatment of AMD and other neurodegenerative diseases. Here we assess the retinoprotective potential of the recently synthesized JNK inhibitor 11
-indeno1,2-
quinoxalin-11-one oxime sodium salt (IQ-1S) using senescence-accelerated OXYS rats as a model of AMD. The treatment with IQ-1S (50 mg/kg body weight intragastric) during the period of active disease development (from 4.5 to 6 months of age) improved some (but not all) histological abnormalities associated with retinopathy. IQ-1S improved blood circulation, increased the functional activity of the retinal pigment epithelium, reduced the VEGF expression in the endothelial cells, and increased the expression of PEDF in the neuroretina. The result was a decrease in the degeneration of photoreceptors and neurons of the inner layers. IQ-1S significantly improved the retinal ultrastructure and increased the number of mitochondria, which were significantly reduced in the neuroretina of OXYS rats compared to Wistar rats. It seems probable that using IQ-1S can be a good prophylactic strategy to treat AMD.
This study investigated the stability of structural motifs via molecular dynamics, using α-α-corners as an example. A molecular dynamics experiment was performed on a sample of α-α-corners selected ...by the authors from the PDB database. For the first time during a molecular dynamics experiment, we investigated the characteristics of structural motifs by describing their geometry, including the interplanar distance, area of polygon of the helices projections intersection, and torsion angles between axes of helices in helical pairs. The torsion angles for the constriction amino acids in the equilibrium portion of the molecular dynamics trajectory were analyzed. Using the molecular dynamics method, α-α-corners were found to be autonomous structures that are stable in aquatic environments.
We analyzed numerically computed velocity autocorrelation functions and generalized frequency spectra of charge distribution in homogeneous DNA sequences at finite temperature. The autocorrelation ...function and generalized frequency spectrum (frequency-dependent diffusion coefficient) are phenomenologically introduced based on the functional of mean-square displacement of the charge in DNA. The charge transfer in DNA was modeled in the framework of the semi-classical Holstein model. In this model, DNA is represented by a chain of oscillators placed into thermostat at a given temperature that is provided by the additional Langevin term. Correspondence to the real DNA is provided by choice of the force parameters, which are calculated with quantum-chemical methods. We computed the diffusion coefficient for all homogenous DNA chains with respect to the temperature and found a special scaling of independent variables that the temperature dependence of the diffusion coefficient for different homogenous DNA is almost similar. Our calculations suggest that for all the sequences, only one parameter of the system is mainly responsible for the charge kinetics. The character of individual motions contributing to the charge mobility and temperature-dependent regimes of charge distribution is determined.
Post-translational modification (PTM) leads to conformational changes in protein structure, modulates the biological function of proteins, and, consequently, changes the signature of metabolic ...transformations and the immune response in the body. Common PTMs are reversible and serve as a mechanism for modulating metabolic trans-formations in cells. It is likely that dysregulation of post-translational cellular signaling leads to abnormal proliferation and oncogenesis. We examined protein PTMs in the blood samples from patients with kidney cancer. Conformational changes in proteins after modification were analyzed. The proteins were analyzed using ultra-high resolution HPLC-MS/MS and structural analysis was performed with the AMBER and GROMACS software packages. Fifteen proteins containing PTMs were identified in blood samples from patients with kidney cancer. For proteins with PDB structures, a comparative analysis of the structural changes accompanying the modifications was performed. Results revealed that PTMs are localized in stable and compact space protein globule motifs that are exposed to a solvent. The phenomenon of modification is accompanied, as a rule, by an increase in the area available for the solvent of the modified amino acid residue and its active environment.
We show that interactions of inherently chaotic oscillators can lead to coexistence of regular oscillatory regimes and chaotic oscillations in the rings of coupled oscillators provided that the level ...of interaction between the oscillators exceeds a threshold value. The transformation of the initially chaotic dynamics into the regular dynamics in a number of the coupled oscillators is shown to result from suppression of chaos by separation of certain oscillation periods from the continuous spectra, which are characteristic of chaotic oscillations.
We analyzed numerically computed velocity autocorrelation functions and generalized frequency spectra of charge distribution in homogeneous DNA sequences at finite temperature. The autocorrelation ...function and generalized frequency spectrum (frequency-dependent diffusion coefficient) are phenomenologically introduced based on the functional of mean-square displacement of the charge in DNA. The charge transfer in DNA was modeled in the framework of the semi-classical Holstein model. In this model, DNA is represented by a chain of oscillators placed into thermostat at a given temperature that is provided by the additional Langevin term. Correspondence to the real DNA is provided by choice of the force parameters, which are calculated with quantum-chemical methods. We computed the diffusion coefficient for all homogenous DNA chains with respect to the temperature and found a special scaling of independent variables that the temperature dependence of the diffusion coefficient for different homogenous DNA is almost similar. Our calculations suggest that for all the sequences, only one parameter of the system is mainly responsible for the charge kinetics. The character of individual motions contributing to the charge mobility and temperature-dependent regimes of charge distribution is determined.
PDF
