Many microtubule-associated proteins (MAPs) function under mechanical loads. Among them, motor proteins and passive couplers link microtubules with other cytoskeletal filaments, membranous structures and diverse scaffolds to enable cell shape changes, locomotion and other important processes. A key kinetochore complex, NDC80, transmits forces from microtubule disassembly to chromosome motion during cell division. Recently, this complex has been shown to detach from microtubules more easily when pulled toward the minus-end of the microtubule than when pulled in the plus-end direction. Here, we used coarse-grained molecular dynamics and Brownian dynamics simulations to explain the asymmetric effect of the directional load on the unbinding of the NDC80 complex from microtubules and then generalized our findings to other MAPs. We found that the lever arm created by the stiff stalk of NDC80 tilted toward the plus-end of the microtubule is critical for asymmetric unbinding of this complex, similar to that of dynein. In contrast, EB-proteins, the microtubule crosslinker PRC1, and kinesins are predicted to lack pronounced unbinding asymmetry, either due to their almost perpendicular anchorage to the microtubule wall or due to the high flexibility of their linker regions proximal to the microtubule-binding domains. Thus, our study highlights some of the design principles of MAPs, explaining how their distal parts can impart, modulate or eliminate the dependence of unbinding on the direction of external loads. This information deepens our understanding of the load-bearing properties and functions of diverse MAPs and may guide the design of synthetic protein systems with predefined mechanical characteristics. ### Competing Interest Statement The authors have declared no competing interest.

Несмотря на широкое распространение и применение препаратов химиотерапии рака, остаются невыясненными молекулярные механизмы действия многих из них. Известно, что некоторые из этих препаратов, например таксол, оказывают влияние на динамику сборки микротрубочек и останавливают процесс клеточного деления в профазе-прометафазе. В последнее время появились новые пространственные структуры микротрубочек и отдельных олигомеров тубулина, связанных с различными регуляторными белками и препаратами химиотерапии рака. Однако знание пространственной структуры само по себе не дает информации о механизме действия препаратов.

In this work, the anti-inflammatory potential of secretory-excretory products (SEP) of gull- tapeworm Dibothriocephalus dendriticus and ligula Ligula interrupta plerocercoids was studied for the first time in an in vitro model of LPS-induced activation of macrophages. A monocyte cell line derived from a patient with acute monocytic leukemia, THP-1, was used as a macrophage model. The anti-inflammatory properties of SEP were determined by the content of tumor necrosis factor (TNF) and interleukin-6 cytokines in the incubation medium using commercial kits for enzyme immunoassay. The results of our study indicated that SEP from L. interrupta plerocercoids have a pronounced anti-inflammatory effect, while SEP from D. dendriticus plerocercoids did not have such an effect. Next, we investigated the anti- inflammatory properties of L. interrupta SEP in a carrageenan-induced air-sac inflammation model in mice. A significant decrease in the volume of inflammatory exudate under the influence of L. interrupta SEP was found, as well as an increase in the level of the interleukin-6 cytokine. At the same time, SEP of L. interrupta had no effect on the number of cells per 1 ml of exudate, as well as on the level of the pro-inflammatory cytokine TNF. The low molecular weight fraction of L. interrupta SEP also increased the level of the anti-inflammatory cytokine interleukin-10, which indicates a more pronounced anti-inflammatory effect compared to the high molecular weight fraction. The results obtained, in general, indicate the anti- inflammatory properties of the SEP of L. interrupta plerocercoids. However, the mechanism of anti-inflammatory action has not been elucidated and requires further research.

Plastocyanin is a small mobile protein that facilitates electron transfer through the formation of short-lived protein-protein complexes with cytochrome bf and photosystem 1. Due to the transient nature of plastocyanin-cytochrome f complex, the lack of a long-lived tight complex makes it impossible to determine its structure by X-ray diffraction analysis. Up to today, a number of slightly different structures of such complexes have been obtained by experimental and computer methods. Now, artificial intelligence gives us the possibility to predict the structures of intermolecular complexes. In this study, we compare encounter and final complexes obtained by Brownian and molecular dynamics methods, as well as the structures predicted by AlphaFold 3, with NMR and cryo-EM data. Surprisingly, the best match for the plastocyanin electron density obtained by cryo-EM was demonstrated by an AlphaFold 3 structure. The orientation of plastocyanin in this structure almost completely coincides with its orientation obtained by molecular dynamics calculation, and, at the same time, it is different from the orientation of plastocyanin predicted on the basis of NMR data. This is even more unexpected given that only NMR structures for the plastocyanin-cytochrome f complex are available in the PDB database, which was used to train AlphaFold 3.

Methylene blue has multiple antiviral properties against Severe Acute Respiratory Syndrome-related Coronavirus 2 (SARS-CoV-2). The ability of methylene blue to inhibit different stages of the virus life cycle, both in light-independent and photodynamic processes, is used in clinical practice. At the same time, the molecular aspects of the interactions of methylene blue with molecular components of coronaviruses are not fully understood. Here, we use Brownian dynamics to identify methylene blue binding sites on the SARS-CoV-2 envelope. The local lipid and protein composition of the coronavirus envelope plays a crucial role in the binding of this cationic dye. Viral structures targeted by methylene blue include the S and E proteins and negatively charged lipids. We compare the obtained results with known experimental data on the antiviral effects of methylene blue to elucidate the molecular basis of its activity against coronaviruses.

Molecular dynamics models of tubulin tetramers in complex with the anticancer drug taxol were created based on high-resolution spatial structures (PDB ID 3J6G). We tested performance of various computational architectures in molecular dynamics calculations of tubulin tetramers. We revealed the optimal computer architecture and carried out three 1 μs molecular dynamic trajectories of taxol-bound tubulin tetramer. We analyzed the conformational flexibility of tubulin tetramers in a complex with taxol, calculated the Euler angles for intra- and inter-dimer interfaces of the protofilament, as well as the degree and direction of protofilament bending. The stiffness of protofilaments was studied using the energy equipartition theorem. The results allowed us to conclude that taxol binding reduces stiffness at both the inter- and intra-dimer interfaces, which may facilitate the process of microtubule assembly.

Inflammatory bowel disease (IBD) is widespread in industrial countries with every 20th citizen being affected. Dysregulation of the epithelial barrier function is considered to play a key role in IBD. Permeability of the intestinal epithelium depends mostly on its self-renewal potential and the condition of intercellular junctions. Mitochondria are involved in regulating various intracellular processes in addition to their energy function. Recent data implicate mitochondria in intestinal epithelial barrier regulation and IBD. Mitochondrial dysfunction is possibly one of the factors that underlie the structural abnormalities of tight junctions and the cytoskeleton in intestinal epithelial cells and decrease the self-renewal capacity of the epithelium. The barrier function of the intestinal epithelium is consequently distorted, and IBD develops. The mechanisms of these processes are still unclear and require further research.

В работе предложен набор достаточно простых алгоритмов, который может быть применен для анализа широкого круга белок-белковых взаимодействий. В настоящей работе мы совместно используем методы броуновской и молекулярной динамики для описания процесса образования комплекса белков пластоцианина и цитохрома f высших растений. В диффузионно-столкновительном комплексе выявлено два кластера структур, переход между которыми возможен с сохранением положения центра масс молекул и сопровождается лишь поворотом пластоцианина на 134 градуса. Первый и второй кластеры структур столкновительных комплексов отличаются тем, что в первом кластере с положительно заряженной областью вблизи малого домена цитохрома f контактирует только «нижняя» область пластоцианина, в то время как во втором кластере — обе отрицательно заряженные области. «Верхняя» отрицательно заряженная область пластоцианина в первом кластере оказывается в контакте с аминокислотным остатком лизина K122. При образовании финального комплекса происходит поворот молекулы пластоцианина на 69 градусов вокруг оси, проходящей через обе области электростатического контакта. При этом повороте происходит вытеснение воды из областей, находящихся вблизи кофакторов молекул и сформированных гидрофобными аминокислотными остатками. Это приводит к появлению гидрофобных контактов, уменьшению расстояния между кофакторами до расстояния менее 1,5 нм и дальнейшей стабилизации комплекса в положении, пригодном для передачи электрона. Такие характеристики, как матрицы контактов, оси поворота при переходе между состояниями и графики изменения количества контактов в процессе моделирования, позволяют определить ключевые аминокислотные остатки, участвующие в формировании комплекса и выявить физико-химические механизмы, лежащие в основе этого процесса.

Severe acute panreatitis is a life-threatening disease with mortality rates of about 15%. With the development of infected necrotizing pancreatitis, complicated by the development of organ failure, the mortality rate is 35.2%. Due to the fact that acute pancreatitis is a highly variable pathological process, leading to a wide range of clinical outcomes, predicting the severity of the disease and early identification of patients at risk of developing severe complications is critical to optimize treatment outcomes for this disease. Currently, there are no uniquely accurate and practically available laboratory tests to predict the severity of patients with acute pancreatitis. The review presents literature data on the terminology and classifications of the severity of acute pancreatitis, taking into account the possibilities of their practical application. Information on clinical scale systems for assessing the severity of acute pancreatitis with an assessment of their effectiveness in predicting various treatment outcomes is presented in detail. The characteristics and capabilities of various laboratory markers in the assessment of organ failure and diagnosis of systemic complications of acute pancreatitis are presented. Currently, for the best assessment of the severity of acute pancreatitis, it is necessary to use a multidisciplinary clinical examination of patients and a combination of various predictive tools.

Molecular dynamics (MD) simulation is a useful tool for understanding biological systems at the level of individual molecules and atoms. However, studying such massive biological systems as microtubules and even their constituent components (tubulin protofilaments) takes an enormous amount of processing power. In this paper, using MD calculations of individual microtubule protofilaments, we demonstrate how computational architecture and calculation options affect computing performance. When using the "GPU-resident" option in the GROMACS MD package, you may gain a fantastic computation acceleration by using the newest high-end graphics processing unit (GPU), even in conjunction with a rather outdated central processing unit (CPU). For instance, MD of the biomolecular system containing a tubulin protofilament in an explicitly specified solvent consisting of more than 300 thousand atoms can be investigated with performance of 171 ns/day at time step 2 fs when using a single-node computer with the latest CPU and GPU generation architecture (Intel Core i9-13900K and Nvidia RTX4090 respectively). Nevertheless, high performance computing platforms (e.g., the volta2 partition of "Lomonosov-2" supercomputer) can be very suitable for simulation experiments with a large number of independent calculations, such as the umbrella sampling technique. Obtained results allow one to choose the best price-performance solution to study molecular dynamics of biological systems.

The Brownian dynamics method can give insight into the initial stages of the interaction of antiviral drug molecules with the structural components of bacteria or viruses. RAM of conventional personal computer allows calculation of Brownian dynamics of interaction of antiviral drugs with individual coronavirus S protein. However, scaling up this approach for modeling the interaction of antiviral drugs with the whole virion consisting of thousands of proteins and lipids is difficult due to high requirements for computing resources. In the case of the Brownian dynamics method, the main amount of RAM in the calculations is occupied by an array of values of the virion electrostatic potential field. When the system is increased from one S protein to the whole virion, the volume of data increases significantly. The standard protocol for calculating Brownian dynamics uses a three-dimensional grid with a spatial step of 1°A to calculate the electrostatic potential field. In this work, we consider the possibility of increasing the grid spacing parameter for calculating the electrostatic potential field of individual coronavirus S proteins. In this case, the amount of RAM occupied by the electrostatic potential field is reduced, which makes it possible to use personal computers for calculations. We performed Brownian dynamics simulations of interaction of an antiviral photosensitizer molecule with S proteins of three coronaviruses SARS-CoV, MERS-CoV, and SARS-CoV-2, and demonstrated that reduction of detalization of electrostatic potential field does not influence the results of Brownian dynamics much © The Authors 2022. This paper is published with open access at SuperFri.org

In patients with acute pancreatitis (AP), diagnostic imaging is very important for determining disease etiology and its primary diagnosis in unclear clinical situations. This review presents literature data about the methodology, indications and timing of various imaging methods in the diagnosis and treatment of AP. The detailed information about modern tomography capabilities in stratification of AP severity and morphological assessment of its local complications is presented. Currently, beam imaging methods are crucial in planning of draining minimally invasive surgical interventions for AP and subsequent assessment of their effectiveness, which makes the radiologist a permanent and key member of a multidisciplinary team of specialists, contributing to the optimization of the immediate and long-term results of treatment of this complex pathology.

Electrostatics is an important part of virus life. Understanding the detailed distribution of charges over the surface of a virus is important to predict its interactions with host cells, antibodies, drugs, and different materials. Using a coarse-grained model of the entire viral envelope developed by D. Korkin and S.-J. Marrink's scientific groups, we created an electrostatic map of the external surface of SARS-CoV-2 and found a highly heterogeneous distribution of the electrostatic potential field of the viral envelope. Numerous negative patches originate mainly from negatively charged lipid domains in the viral membrane and negatively charged areas on the "stalks" of the spike (S) proteins. Membrane (M) and envelope (E) proteins with the total positive charge tend to colocalize with the negatively charged lipids. In the E protein pentamer exposed to the outer surface, negatively charged glutamate residues and surrounding lipids form a negative electrostatic potential ring around the channel entrance. We simulated the interaction of the antiviral octacationic photosensitizer octakis(cholinyl)zinc phthalocyanine with the surface structures of the entire model virion using the Brownian dynamics computational method implemented in ProKSim software (version r661). All mentioned negatively charged envelope components attracted the photosensitizer molecules and are thus potential targets for reactive oxygen generated in photosensitized reactions.

The research review presents literature data on the possibilities of performing minimally invasive necrosectomy for infected forms of acute necrotizing pancreatitis. The paper provides detailed information concerning the terminology, indications for, and technical features of implementing the principal methods of minimally invasive surgical debridement of necrotic accumulations. The techniques include endoscopic transluminal necrosectomy, videoassisted retroperitoneal debridement, and minimally invasive retroperitoneal necrosectomy. The review describes results of numerous studies on the evaluation of their effectiveness and possible options for their combined use. Additionally, we present the materials of relevant international clinical guidelines which indicate the viability of performing minimally invasive necrosectomy as part of a phased strategy for the treatment of patients with acute necrotizing pancreatitis.

Summarized results of investigation of regulation of electron transport and associated processes in the photosynthetic membrane using methods of mathematical and computer modeling carried out at the Department of Biophysics, Faculty of Biology, Lomonosov Moscow State University, are presented in this review. Detailed kinetic models of processes in the thylakoid membrane were developed using the apparatus of differential equations. Fitting of the model curves to the data of spectral measurements allowed us to estimate the values of parameters that were not determined directly in experiments. The probabilistic method of agent-based Monte Carlo modeling provides ample opportunities for studying dynamics of heterogeneous systems based on the rules for the behavior of individual elements of the system. Algorithms for simplified representation of Big Data make it possible to monitor changes in the photosynthetic apparatus in the course of culture growth in a photobioreactor and for the purpose of environmental monitoring. Brownian and molecular models describe movement and interaction of individual electron carrier proteins and make it possible to study electrostatic, hydrophobic, and other interactions leading to regulation of conformational changes in the reaction complexes. Direct multiparticle models explicitly simulate Brownian diffusion of the mobile protein carriers and their electrostatic interactions with multienzyme complexes both in solution and in heterogeneous interior of a biomembrane. The combined use of methods of kinetic and Brownian multiparticle and molecular modeling makes it possible to study the mechanisms of regulation of an integral system of electron transport processes in plants and algae at molecular and subcellular levels.

The paper presents the results of recent work at the Department of Biophysics of the Biological Faculty, Lomonosov Moscow State University on the kinetic and multiparticle modeling of processes in the photosynthetic membrane. The detailed kinetic models and the rule-based kinetic Monte Carlo models allow to reproduce the fluorescence induction curves and redox transformations of the photoactive pigment P700 in the time range from 100 ns to dozens of seconds and make it possible to reveal the role of individual carriers in their formation for different types of photosynthetic organisms under different illumination regimes, in the presence of inhibitors, under stress conditions. The fitting of the model curves to the experimental data quantifies the reaction rate constants that cannot be directly measured experimentally, including the non-radiative thermal relaxation reactions. We use the direct multiparticle models to explicitly describe the interactions of mobile photosynthetic carrier proteins with multienzyme complexes both in solution and in the biomembrane interior. An analysis of these models reveals the role of diffusion and electrostatic factors in the regulation of electron transport, the influence of ionic strength and pH of the cellular environment on the rate of electron transport reactions between carrier proteins. To describe the conformational intramolecular processes of formation of the final complex, in which the actual electron transfer occurs, we use the methods of molecular dynamics. The results obtained using kinetic and molecular models supplement our knowledge of the mechanisms of organization of the photosynthetic electron transport processes at the cellular and molecular levels.

Microtubules are non-covalent polymers of αβ-tubulin dimers. Posttranslational processing of the intrinsically disordered C-terminal α-tubulin tail produces detyrosinated and Δ2-tubulin. Although these are widely employed as proxies for stable cellular microtubules, their effect (and of the α-tail) on microtubule dynamics remains uncharacterized. Using recombinant, engineered human tubulins, we now find that neither detyrosinated nor Δ2-tubulin affect microtubule dynamics, while the α-tubulin tail is an inhibitor of microtubule growth. Consistent with the latter, molecular dynamics simulations show the α-tubulin tail transiently occluding the longitudinal microtubule polymerization interface. The marked differential in vivo stabilities of the modified microtubule subpopulations, therefore, must result exclusively from selective effector recruitment. We find that tyrosination quantitatively tunes CLIP-170 density at the growing plus end and that CLIP170 and EB1 synergize to selectively upregulate the dynamicity of tyrosinated microtubules. Modification-dependent recruitment of regulators thereby results in microtubule subpopulations with distinct dynamics, a tenet of the tubulin code hypothesis.

Photodynamic inactivation of pathogenic microorganisms can be successfully used to eradicate pathogens in localized lesions, infected liquid media, and on various surfaces. This technique utilizes the photosensitizer (PS), light, and molecular oxygen to produce reactive oxygen species that kill pathogens. Here, we used the PS, water soluble octakis(cholinyl)zinc phthalocyanine (Zn-PcChol8+), to inactivate an initial 4.75–5.00 IgTCID50/mL titer of SARS-CoV-2, thereby preventing viral infection when tested in Vero E6 cell cultures. Zn-PcChol8+ in a minimally studied concentration, 1 µM and LED 3.75 J/cm2, completely destroyed the infectivity of SARS-CoV-2. To detect possible PS binding sites on the envelope of SARS-CoV-2, we analyzed electrostatic potential and simulated binding of Zn-PcChol8+ to the spike protein of this coronavirus by means of Brownian dynamics software, ProKSim (Protein Kinetics Simulator). Most of the Zn-PcChol8+ molecules formed clusters at the upper half of the stalk within a vast area of negative electrostatic potential. Positioning of the PS on the surface of the spike protein at a distance of no more than 10 nm from the viral membrane may be favorable for the oxidative damage. The high sensitivity of SARS-CoV-2 to photodynamic inactivation by Zn-PcChol8+ is discussed with respect to the application of this PS to control the spread of COVID-19.