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Molecular Modeling of Penicillin Acylase Binding with a Penicillin Nucleus by High Performance Computing: Can Enzyme or its Mutants Possess β-lactamase Activity?

Supercomputing Frontiers and Innovations

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Supercomputing Frontiers and Innovations 2022年第2期9卷 68-78页

作者： Kirilin, Evgeny M. Bochkova, Anna A. Panin, Nikolay V. Pochinok, Igor V. Švedas, Vytas Lomonosov Moscow State University Belozersky Institute of Physicochemical Biology Moscow Russia Lomonosov Moscow State University Research Computing Center Moscow Russia Lomonosov Moscow State University Faculty of Bioengineering and Bioinformatics Moscow Russia

High-performance computing has been used for molecular modeling of penicillin acylase interaction with a penicillin nucleus 6-aminopenicillanic acid (6-APA) to assess whether the wild-type enzyme or its mutants could possess β-lactamase activity. Applying parallel hybrid GPU/CPU computing technologies for metadynamics calculations with the PLUMED library in conjunction with AMBER software suite it has been shown that trace amounts of wild-type penicillin acylas-e6-APA complexes leading to a β-lactamase reaction can be formed. Higher β-lactamase activity can be observed in enzyme mutants by introducing charged residue in the substrate binding pocket and its proper positioning with respect to a catalytic nucleophile, including stabilization of the tetrahedral intermediate in the oxyanion hole. Thus, it has been shown that the certain mutations facilitate the orientation of the substrate required for the manifestation of β-lactamase activity in the penicillin acylase active center. © The Authors 2022. This paper is published with open access at ***

关键词： Molecular modeling

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Limits on inferring gene regulatory networks from single-cell measurements of unstable mRNA levels

Limits on inferring gene regulatory networks from single-cel...

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IEEE Conference on Decision and Control

作者： Tarun Mahajan Michael Saint-Antoine Roy D. Dar Abhyudai Singh Department of Bioengineering University of Illinois at Urbana-Champaign Urbana IL USA Center for Bioinformatics and Computational Biology University of Delaware Newark DE USA Faculty of Department of Bioengineering University of Illinois at Urbana-Champaign Urbana IL USA Faculty of Electrical and Computer Engineering Biomedical Engineering and Mathematical Sciences University of Delaware Newark DE USA

ISBN: (数字)9781665467612

ISBN: (纸本)9781665467629

Gene regulatory network inference from single-cell expression data, such as single-cell RNA sequencing, is a popular problem in computational biology. Despite diverse methods spanning information theory, machine learning, and statistics, it is unsolved. This is attributable to measurement errors, lack of perturbation data, or difficulty in causal inference. Yet the role of kinetic parameters of gene expression is unknown. We show how the relative stability of mRNA and protein hampers inference. We use a simple model of gene expression to show that a more stable protein than mRNA deteriorates correlation between the mRNA of a transcription factor and its target gene. This can also happen when mRNA and protein are on the same timescale. Relative difference in timescales affects true interactions more strongly than false positives. Besides correlation, we find that information-theoretic nonlinear measures are also prone to this problem.

关键词： Proteins Sequential analysis Measurement errors Correlation RNA Perturbation methods Machine learning

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Cryo-EM structure of the bullet-shaped GroEL-GroES complex at 3.6 Å resolution

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Microscopy and Microanalysis 2021年第S1期27卷 1120-1121页

作者： Evgeny Pichkur Sofia Kudryavtseva Igor Yaroshevich Vladimir Muronetz Olga Sokolova Tatiana Stanishneva-Konovalova 1National Research Center “Kurchatov Institute” United States Lomonosov Moscow State University Faculty of Bioengineering and Bioinformatics United States Lomonosov Moscow State University United States Moscow Lomonosov University United States

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Making Synchrosqueezing Locally Adaptive in The Time-Frequency Plane

Making Synchrosqueezing Locally Adaptive in The Time-Frequen...

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International Conference on Acoustics, Speech, and Signal Processing (ICASSP)

作者： Marcelo A. Colominas Sylvain Meignen Universidad Nacional de Entre Ríos (UNER) Faculty of Engineering Institute for Research and Development in Bioengineering and Bioinformatics (IBB) CONICET Argentina Jean Kuntzmann Laboratory University Grenoble Alpes and CNRS France

In this work, we explore the problem of making synchrosqueezing transform adaptive. To deal with multicomponent signals, existing methods use a fixed order N, thus assuming all the modes making up the signal have order N polynomial phases. To go beyond this limitation, we introduce a new criterion based on the concentration of the representation to locally choose the best order for the synchrosqueezing transform. We study the performance of the proposed approach in terms of the error with respect to the ideal time-frequency representation, both on synthetic and real signals.

关键词： Greedy algorithms Time-frequency analysis Transforms Signal processing Acoustics Proposals Speech processing

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Computational Alchemy Using Accelerated GPU Calculations: Fine Structural Tuning Inhibitors of L,D-transpeptidase 2 from Mycobacterium tuberculosis

Supercomputing Frontiers and Innovations

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Supercomputing Frontiers and Innovations 2022年第3期9卷 72-86页

作者： Baldin, Semen M. Shegolev, Vsevolod O. Švedas, Vytas K. Lomonosov Moscow State University Belozersky Institute of Physicochemical Biology Moscow Russia Lomonosov Moscow State University Research Computing Center Moscow Russia Lomonosov Moscow State University Faculty of Chemistry Moscow Russia Lomonosov Moscow State University Faculty of Bioengineering and Bioinformatics Moscow Russia

The computational alchemy is based on equilibrium methods of molecular dynamics (MD), including thermodynamic integration (TI) or free energy perturbation (FEP). It makes it possible to evaluate the energy characteristics of a subtile alchemical transformation of the prototype compound structures in order to modulate their functional properties, what can be used searching for new analogues of enzyme inhibitors. In recent years, the method is gaining new opportunities due to high-performance computing as different MD engines got the ability to perform TI or FEP calculations using GPU acceleration. We have tested the method on two experimentally studied enzyme-inhibitor systems: penicillin acylase from E. coli (PaEc) and Influenza A virus neuraminidase (NaIAv) and performed computational alchemy calculations for pairs of their known inhibitors. Thus, the validated methodology was then applied to estimate binding of L,Dtranspeptidase 2 from M. tuberculosis (LdtMt2) to the structural analogs of inhibitors previously discovered in our group. We have found that the performance of computational alchemy predictions is highly dependent on properly chosen simulation parameters and at optimal performance the difference between the calculated and experimentally determined relative binding energies is less than 1 kcal/mol. Thus, for optimal application to novel enzyme—inhibitor or receptor—ligand systems, we recommend prior adaptation of this method, based on validation of force field combinations as well as water models, to experimentally determined binding data of structurally related inhibitors/ligands to the molecular target of interest, if available, and then to proceed to the study of new compounds. High-performance computational alchemy can be used as a useful integrative part of the methodology searching for new enzyme inhibitors or receptor ligands and optimizing their structure at drug design © The Authors 2022. This paper is published with open access at ***

关键词： Molecular dynamics

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Translating from Na to Ca : Na/Ca-exchanger exerts Na -dependent control over astrocytic Ca oscillations

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The European Physical Journal Plus 2021年第7期136卷 1-16页

作者： Verisokin, Andrey Yu. Verveyko, Darya V. Kucherenko, Varvara V. Postnov, Dmitry E. Brazhe, Alexey R. Department of Theoretical Physics Kursk State University Kursk Russia Faculty of Bioengineering and Bioinformatics Lomonosov Moscow State University Moscow Russia Saratov State National Research University Saratov Russia Biological Faculty Lomonosov Moscow State University Moscow Russia Department of Molecular Neurobiology Institute of Bioorganic Chemistry RAS Moscow Russia

Recently accumulated evidences suggest that astrocyte signaling is in touch link with extracellular volume regulation and interstitial fluid drainage from the brain. Classical understanding of astrocyte activity is based on IP $$_3$$ -dependent calcium exchange with intracellular stores. Recent evidence shifts focus to calcium entry from extracellular space via multiple mechanisms and widens it to taking other ions into account. It has been hypothesized that Na/Ca-exchanger can translate activity-dependent Na $$^+$$ transients into modulation of Ca $$^{2+}$$ dynamics. We combine a model of IP $$_3$$ -based Ca $$^{2+}$$ dynamics with a model of Ca $$^{2+}$$ flow through Na/Ca-exchanger to provide theoretical insights into the possible effects of such modulation. We find that the exchanger can provide for bidirectional Na $$^+$$ -dependent modulation of the sensitivity to extracellular glutamate, oscillation amplitude and frequency modulation, as well as extending the available set of dynamical regimes. The extent of the emergent Na $$^+$$ sensitivity is predicted to be scaled by a morphology-dependent balance between the maximal flow through the exchanger and the rate of entry from intracellular stores.

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Osteogenic activity of bone: Novel approach of polyvinylidene fluoride films, marrow blood supply, and ultrasound stimulation

SPE Polymers

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SPE Polymers 2023年第4期4卷 175-185页

作者： Zuchuat, Jésica Halter, Christian Zalazar, Martín Faculty of Engineering National University of Entre Ríos Entre Ríos Argentina Institute for Research and Development in Bioengineering and Bioinformatics UNER – CONICET Entre Ríos Argentina

Electric fields used in bone stimulation are based on the application of direct current, but some drawbacks exist, such as the need for an external power source. Piezoelectric poly(vinylidene fluoride) (PVDF) has attracted interest for biomedical applications due to its flexibility, low toxicity, and the piezoelectric response to mechanical stimuli. This study aimed to investigate the effects of PVDF films on bone regeneration in rabbit tibias to assess the potential improvement in osteogenesis. An initial exploratory experiment was performed to determine optimal parameters for regulating the marrow blood supply. The second experiment focused on examining the effects of ultrasound stimulation on the implant's osteogenic capacity. The results showed that PVDF films have a notable impact on the extraskeletal bone formation and bone density in a secluded microenvironment with and without microperforations. At 60 days after surgery, tibias with marrow blood supply reached higher bone volumes and density and they were consistent with the cellular activity. Our results suggest that piezoelectric PVDF films have osteogenic characteristics and can be used to enhance new bone formation in a secluded space, thus reinforcing their biocompatibility nature. Additional studies are required to analyze the benefits of ultrasound stimulation. © 2023 The Authors. SPE Polymers published by Wiley Periodicals LLC on behalf of Society of Plastics Engineers.

关键词： bone tissue engineering osteogenesis piezoelectric polyvinylidene fluoride ultrasound

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Modulatory effect of NCX on IP3-dependent Ca2+oscillations in astrocytes

Modulatory effect of NCX on IP3-dependent Ca2+oscillations i...

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Saratov Fall Meeting 2020 - Computations and Data Analysis: From Molecular Processes to Brain Functions

作者： Verisokin, Andrey Yu. Verveyko, Darya V. Kucherenko, Varvara V. Postnov, Dmitry E. Brazhe, Alexey R. Department of Theoretical Physics Kursk State University Radishcheva st. 33 Kursk305000 Russia Saratov State National Research University Astrakhanskaya st. 83 Saratov Russia Biological Faculty Lomonosov Moscow State University Leninskie Gory 1/24 Moscow Russia Faculty of Bioengineering and Bioinformatics Lomonosov Moscow State University Leninskie Gory 1/73 Moscow Russia Department of Molecular Neurobiology Institute of Bioorganic Chemistry RAS Miklukho-Maklay str 16/10 Moscow Russia

ISBN: (纸本)9781510645325

Most of the existing models of calcium dynamics of astrocytes do not take into account the effect of the Na/Ca- exchanger on the formation of calcium oscillations and their properties. However, recent experimental studies show that at an increased sodium concentration, the Na/Ca-exchanger works in the reverse mode, providing an additional calcium entry into the cell cytosol. In this work we study a model that simultaneously takes into account the IP3-mediated exchange with intracellular [Ca2+] stores and bidirectional [Ca2+] flow through Na/Ca-exchanger. We analyze the behavior of the system under stimulation with external glutamate- of the cell, explore the possible behavior regimes and reveal the effect of the cytosolic sodium concentration, the maximum current through the Na/Ca-exchanger, and the stimulus amplitude on the astrocytic calcium dynamics. © COPYRIGHT SPIE. Downloading of the abstract is permitted for personal use only.

关键词： Sodium

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A Hybrid of Bat Algorithm and Minimization of Metabolic Adjustment for Succinate and Lactate Production 14th

A Hybrid of Bat Algorithm and Minimization of Metabolic Adju...

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14th International Conference on Practical Applications of Computational Biology and bioinformatics, PACBB 2020

作者： Man, Mei Yen Mohamad, Mohd Saberi Choon, Yee Wen Ismail, Mohd Arfian Artificial Intelligence and Bioinformatics Research Group Faculty of Computing Universiti Teknologi Malaysia SkudaiJohor81310 Malaysia Institute for Artificial Intelligence and Big Data Universiti Malaysia Kelantan City Campus Pengkalan Chepa Kota BharuKelantan16100 Malaysia Faculty of Bioengineering and Technology Universiti Malaysia Kelantan Jeli Campus JeliKelantan17600 Malaysia College of Computing and Applied Sciences Universiti Malaysia Pahang Lebuhraya Tun Razak Gambang KuantanPahang Darul Makmur26300 Malaysia

ISBN: (纸本)9783030545673

The elementary concept of metabolic engineering is to manipulate those potential genes to augment the yields of metabolite production by restructuring and deregulating the metabolic networks. However, the yields of biochemical products are far below their theoretical maximums, although many conventional methods that have been introduced. These conventional methods had encountered problems in getting stuck at a local minimum. This paper proposes a hybrid of the Bat Algorithm (BAT) and the Minimization of Metabolic Adjustment (MOMA) to predict an ideal set of solutions in order to improve the production of succinate and lactate. The dataset utilized in this paper was the Escherichia coli core model, which is the subset of the iAF1260 E. coli metabolic network. The experimental results include the production rate, growth rate, and a list of knockout genes. From the comparative analysis, BATMOMA has better performance in terms of production rate compared to previous works, proving that it has the potential for resolving genetic engineering problems. © 2021, The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG.

关键词： Metabolic engineering

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Identification of hedgehog signaling as a potential oncogenic driver in an aggressive subclass of human hepatocellular carcinoma: A reanalysis of the TCGA cohort

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Science China(Life Sciences) 2019年第11期62卷 1481-1491页

作者： Yang Zhao Li Zhang Yong Zhang Bo Meng Wantao Ying Xiaohong Qian College of Life Science and Bioengineering Beijing University of TechnologyBeijing 100124China State Key Laboratory of Proteomics Beijing Proteome Research CenterNational Center for Protein Sciences(Beijing)Beijing Institute of LifeomicsBeijing 102206China Center for Bioinformatics and Computational Biology Institute of Biomedical SciencesSchool of Life SciencesEast China Normal UniversityShanghai 200241China School of Statistics Faculty of Economics and ManagementEast China Normal UniversityShanghai 200241China Key Lab of Transplant Engineering and Immunology West China-Washington Mitochondria and Metabolism Research CenterWest China HospitalSichuan UniversityChengdu 610041China

Hepatocellular carcinoma(HCC)is a heterogeneous disease and the second most common cause of cancer-related death *** developments in genomic technologies helped scientists to understand the heterogeneity of HCC and identified multiple HCC-related molecular *** integrative analysis of genomic datasets including 196 patients from The Cancer Genome Atlas(TCGA)group has recently reported a new HCC subclass,which contains three subgroups(iCluster1,iCluster2,and iCluster3).However,the transcriptional molecular characteristics underlying the iClusters have not been thoroughly ***,we identified a more aggressive subset of HCC patients in the iCluster1,and re-clustered the TCGA samples into novel HCC subclasses referred to as aggressive(Ag),moderate-aggressive(M-Ag),and less-aggressive(L-Ag)*** Ag subclass had a greater predictive power than the TCGA iCluster1,and a higher level of alpha fetoprotein,microscopic vascular invasion,immune infiltration,isocitrate dehydrogenase 1/2 mutation status,and a worse survival than MAg and L-Ag *** transcriptomic analysis showed that activation of hedgehog signaling in the Ag subclass may play key roles in tumor development of aggressive ***1,a key transcriptional regulator of hedgehog signaling upregulated in the Ag subclass,was correlated with poor prognosis of HCC,and may be a potential prognostic biomarker and therapeutic target for Ag subclass HCC patients.

关键词： hepatocellular carcinoma The Cancer Genome Atlas molecular subclass Wnt hedgehog

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