Anton O. Chugunov

Education

PeriodCountry, cityEducation institutionAdditional info
1994–1998 Russia, Zelenograd Ph.-Math. School Finished with honors
1998–2003 Russia, Moscow Moscow State University, biological faculty, department of biophysics Ms in biophysics (with honors). Thesis: Molecular modeling of human MT1 and MT2 melatonin receptors
2003–2006 Russia, Moscow Moscow State University, biological faculty, department of biophysics PhD in physics & mathematics (thesis: Novel approaches to molecular modeling of transmembrane domains of GPCR-receptors)
2008 Brussels, Belgium Post-doc in Université Libre de Bruxelles Modeling of spatial structure of complex of vasoactive intestinal peptide (VIP) with its receptor (GPCR-B family)  as a part of a project for design of selective neoreceptor– neoligand couple

Grants & projects

PeriodAdditional info
2008–2009 Grant of the president of Russian Federation
2010–2012 State contract "Design of novel peptide ligands of sodium channels — an instruments for neurobiology research"
2012–2014 Stipend of the president of Russian Federation
2014–2015 RFBR grant 14-04-31634 “’Protein surface topography’ — a novel tool in bioactive peptides structure–function research”

Selected publications

  1. Chugunov A.O., Volynsky P.E., Krylov N.A., Nolde D.E., Efremov R.G. (2016). Temperature-sensitive gating of TRPV1 channel as probed by atomistic simulations of its trans- and juxtamembrane domains. Sci Rep 6, 33112 [+]

    Heat-activated transient receptor potential channel TRPV1 is one of the most studied eukaryotic proteins involved in temperature sensation. Upon heating, it exhibits rapid reversible pore gating, which depolarizes neurons and generates action potentials. Underlying molecular details of such effects in the pore region of TRPV1 is of a crucial importance to control temperature responses of the organism. Despite the spatial structure of the channel in both open (O) and closed (C) states is known, microscopic nature of channel gating and mechanism of thermal sensitivity are still poorly understood. In this work, we used unrestrained atomistic molecular dynamics simulations of TRPV1 (without N- and C-terminal cytoplasmic domains) embedded into explicit lipid bilayer in its O- and C-states. We found that the pore domain with its neighboring loops undergoes large temperature-dependent conformational transitions in an asymmetric way, when fragments of only one monomer move with large amplitude, freeing the pore upon heating. Such an asymmetrical gating looks rather biologically relevant because it is faster and more reliable than traditionally proposed "iris-like" symmetric scheme of channel opening. Analysis of structural, dynamic, and hydrophobic organization of the pore domain revealed entropy growth upon TRPV1 gating, which is in line with current concepts of thermal sensitivity.

    ID:1558
  2. Lyukmanova E.N., Shenkarev Z.O., Shulepko M.A., Paramonov A.S., Chugunov A.O., Janickova H., Dolejsi E., Dolezal V., Utkin Y.N., Tsetlin V.I., Arseniev A.S., Efremov R.G., Dolgikh D.A., Kirpichnikov M.P. (2015). Structural Insight into Specificity of Interactions between Nonconventional Three-finger Weak Toxin from Naja kaouthia (WTX) and Muscarinic Acetylcholine Receptors. J. Biol. Chem. 290 (39), 23616–30 [+]

    Weak toxin from Naja kaouthia (WTX) belongs to the group of nonconventional "three-finger" snake neurotoxins. It irreversibly inhibits nicotinic acetylcholine receptors and allosterically interacts with muscarinic acetylcholine receptors (mAChRs). Using site-directed mutagenesis, NMR spectroscopy, and computer modeling, we investigated the recombinant mutant WTX analogue (rWTX) which, compared with the native toxin, has an additional N-terminal methionine residue. In comparison with the wild-type toxin, rWTX demonstrated an altered pharmacological profile, decreased binding of orthosteric antagonist N-methylscopolamine to human M1- and M2-mAChRs, and increased antagonist binding to M3-mAChR. Positively charged arginine residues located in the flexible loop II were found to be crucial for rWTX interactions with all types of mAChR. Computer modeling suggested that the rWTX loop II protrudes to the M1-mAChR allosteric ligand-binding site blocking the entrance to the orthosteric site. In contrast, toxin interacts with M3-mAChR by loop II without penetration into the allosteric site. Data obtained provide new structural insight into the target-specific allosteric regulation of mAChRs by "three-finger" snake neurotoxins.

    ID:1394
  3. Kasheverov I.E., Kudryavtsev D.S., Ivanov I.A., Zhmak M.N., Chugunov A.O., Tabakmakher V.M., Zelepuga E.A., Efremov R.G., Tsetlin V.I. (2015). Rational design of new ligands for nicotinic receptors on the basis of α-conotoxin PnIA. Dokl. Biochem. Biophys. 461, 106–9 [+]

    A variety of different subtypes of nicotinic acetylcholine receptors (nAChRs) and their involvement in a number of diseases and pathologies (Parkinson’s and Alzheimer’s diseases, schizophrenia, myasthenia, nicotine addiction) dictates the needs in potent and selective ligands for each subtype. These ligands can be used as a tool for detection and characterization of the distinct nAChR subtypes, as well as be the basis for drug design. Novel cholinergic ligands can emerge in the result of search among natural sources or design (with the use of modern computer modeling) on the basis of known molecules. The significance of the first way was confirmed in our hands by the detection of affinities of a set of marine alkaloids from sponges and ascidians towards some receptor subtypes. The most active of them — makaluvamines — showed micromolar affinity for muscle and neuronal α7 nAChRs. Application of the recently presented Protein Surface Topography method to known natural antagonist of some neuronal nAChRs — α-conotoxin PnIA — resulted in design of new potent analogs with nanomolar affinities for α7 nAChR. Radioactive derivatives of these analogs were successfully applied in radioligand tests for characterization of novel compounds and could be perspective as well for detection of α7 nAChR in the various preparations. Combining these two ways (search and design) was demonstrated in the synthesis of small peptide compounds on the basis of discovered by us in venom of Burmese Viper linear peptide azemiopsin — powerful blocker of muscle-type nAChRs. Some designed peptides have retained a certain affinity to receptor and showed high practical potential: in the absence of toxicity they contributed to the reduction of facial wrinkles (patent application for cosmetic use RU2013102410; PCT/RU2014/000032).

    ID:1393
  4. Чугунов А.О., Ефремов Р.Г. (2014). Поверхность молекулы -- источник биологической информации. Природа  (10), 3–10 [+]

    Компьютерное моделирование биологических молекул зачастую основано не на квантовой механике, описывающей строение вещества максимально корректно, а на наборе приближений, уводящих нас от физических «истоков», но позволяющих решать практически важные задачи с использованием ЭВМ. Одним из таких упрощений является концепция молекулярных поверхностей, представляющая молекулу в виде твердого тела, на поверхности которого распределены какие-либо физические свойства. Несмотря на кажущийся примитивизм, этот подход является довольно плодотворным, внося свою лепту в решение актуальных проблем молекулярной биологии, — например, дизайна новых антибиотиков и изучения молекулярных механизмов заболеваний.

    ID:1092
  5. Koromyslova A.D., Chugunov A.O., Efremov R.G. (2014). Deciphering Fine Molecular Details of Proteins' Structure and Function with a Protein Surface Topography (PST) Method. Journal of chemical information and modeling 54 (4), 1189–99 [+]

    Molecular surfaces are the key players in biomolecular recognition and interactions. Nowadays, it is trivial to visualize a molecular surface and surface-distributed properties in three-dimensional space. However, such a representation trends to be biased and ambiguous in case of thorough analysis. We present a new method to create 2D spherical projection maps of entire protein surfaces and manipulate with them-protein surface topography (PST). It permits visualization and thoughtful analysis of surface properties. PST helps to easily portray conformational transitions, analyze proteins' properties and their dynamic behavior, improve docking performance, and reveal common patterns and dissimilarities in molecular surfaces of related bioactive peptides. This paper describes basic usage of PST with an example of small G-proteins conformational transitions, mapping of caspase-1 intersubunit interface, and intrinsic "complementarity" in the conotoxin-acetylcholine binding protein complex. We suggest that PST is a beneficial approach for structure-function studies of bioactive peptides and small proteins.

    ID:1030
  6. Polyansky A.A., Chugunov A.O., Volynsky P.E., Krylov N.A., Nolde D.E., Efremov R.G. (2014). PREDDIMER: a web server for prediction of transmembrane helical dimers. Bioinformatics 30 (6), 889–90 [+]

    Here we present PREDDIMER, a web tool for prediction of dimer structure of transmembrane (TM) helices. PREDDIMER allows (i) reconstruction of a number of dimer structures for given sequence(s) of TM protein fragments, (ii) ranking and filtering of predicted structures according to respective values of a scoring function, (iii) visualization of predicted 3D dimer structures and (iv) visualization of surface hydrophobicity of TM helices and their contacting (interface) regions represented as 2D maps.

    ID:975
  7. Chugunov A.O., Volynsky P.E., Krylov N.A., Boldyrev I.A., Efremov R.G. (2014). Liquid but Durable: Molecular Dynamics Simulations Explain the Unique Properties of Archaeal-Like Membranes. Sci Rep 4, 7462 [+]

    Archaeal plasma membranes appear to be extremely durable and almost impermeable to water and ions, in contrast to the membranes of Bacteria and Eucaryota. Additionally, they remain liquid within a temperature range of 0-100°C. These are the properties that have most likely determined the evolutionary fate of Archaea, and it may be possible for bionanotechnology to adopt these from nature. In this work, we use molecular dynamics simulations to assess at the atomistic level the structure and dynamics of a series of model archaeal membranes with lipids that have tetraether chemical nature and "branched" hydrophobic tails. We conclude that the branched structure defines dense packing and low water permeability of archaeal-like membranes, while at the same time ensuring a liquid-crystalline state, which is vital for living cells. This makes tetraether lipid systems promising in bionanotechnology and material science, namely for design of new and unique membrane nanosystems.

    ID:1110
  8. Чугунов А.О., Василевский А.А. (2013). Эволюционная «гонка вооружений»: нейротоксины против ионных каналов. Наука и Жизнь 11, 42–48 [+]

    Биологическая эволюция — общая форма существования живой материи. При детальном рассмотрении оказывается, что виды почти никогда не эволюционируют поодиночке. Обычно в этом принимают участие их экологические партнёры. Таким образом, изменение происходит в парах: паразит — хозяин, хищник — жертва. Эволюционное изменение одного вида неизбежно приводит к изменению другого. Более того, взаимную эволюцию, когда один вид совершенствует систему нападения, а другой вслед за ним — систему защиты (и наоборот), часто можно проследить на молекулярном уровне. И здесь наиболее действенной и элегантной оказалась система нападения с помощью ядов, содержащих в своём составе нейротоксины — вещества, воздействующие на нервную систему и мышцы жертвы.

    ID:976
  9. Chugunov A.O., Koromyslova A.D., Berkut A.A., Peigneur S., Tytgat J., Polyansky A.A., Pentkovsky V.M., Vassilevski A.A., Grishin E.V., Efremov R.G. (2013). Modular Organization of α-Toxins from Scorpion Venom Mirrors Domain Structure of Their Targets, Sodium Channels. J. Biol. Chem. 288 (26), 19014–27 [+]

    To gain success in the evolutionary "arms race," venomous animals such as scorpions produce diverse neurotoxins selected to hit targets in the nervous system of prey. Scorpion α-toxins affect insect and/or mammalian voltage-gated sodium channels (Navs) and thereby modify the excitability of muscle and nerve cells. Although more than 100 α-toxins are known and a number of them have been studied into detail, the molecular mechanism of their interaction with Navs is still poorly understood. Here, we employ extensive molecular dynamics simulations and spatial mapping of hydrophobic/hydrophilic properties distributed over the molecular surface of α-toxins. It is revealed that despite the small size and relatively rigid structure, these toxins possess modular organization from structural, functional, and evolutionary perspectives. The more conserved and rigid "core module" is supplemented with the "specificity module" (SM) that is comparatively flexible and variable and determines the taxon (mammal versus insect) specificity of α-toxin activity. We further show that SMs in mammal toxins are more flexible and hydrophilic than in insect toxins. Concomitant sequence-based analysis of the extracellular loops of Navs suggests that α-toxins recognize the channels using both modules. We propose that the core module binds to the voltage-sensing domain IV, whereas the more versatile SM interacts with the pore domain in repeat I of Navs. These findings corroborate and expand the hypothesis on different functional epitopes of toxins that has been reported previously. In effect, we propose that the modular structure in toxins evolved to match the domain architecture of Navs.

    ID:858
  10. Chugunov A., Pyrkova D., Nolde D., Polyansky A., Pentkovsky V., Efremov R. (2013). Lipid-II forms potential "landing terrain" for lantibiotics in simulated bacterial membrane. Sci Rep 3, 1678 [+]

    Bacterial cell wall is targeted by many antibiotics. Among them are lantibiotics, which realize their function via interaction with plasma membrane lipid-II molecule - a chemically conserved part of the cell wall synthesis pathway. To investigate structural and dynamic properties of this molecule, we have performed a series of nearly microsecond-long molecular dynamics simulations of lipid-II and some of its analogs in zwitterionic single component and charged mixed simulated phospholipid bilayers (the reference and the mimic of the bacterial plasma membrane, respectively). Extensive analysis revealed that lipid-II forms a unique "amphiphilic pattern" exclusively on the surface of the simulated bacterial membrane (and not in the reference one). We hypothesize that many lantibiotics exploit the conserved features of lipid-II along with characteristic modulation of the bacterial membrane as the "landing site". This putative recognition mechanism opens new opportunities for studies on lantibiotics action and design of novel armament against resistant bacterial strains.

    ID:839
  11. Aseev L.V., Chugunov A.O., Efremov R.G., Boni I.V. (2013). A single missense mutation in a coiled-coil domain of Escherichia coli ribosomal protein S2 confers a thermosensitive phenotype that can be suppressed by ribosomal protein S1. J. Bacteriol. 195 (1), 95–104 [+]

    Ribosomal protein S2 is an essential component of translation machinery, and its viable mutated variants conferring distinct phenotypes serve as a valuable tool in studying the role of S2 in translation regulation. One of a few available rpsB mutants, rpsB1, shows thermosensitivity and ensures enhanced expression of leaderless mRNAs. In this study, we identified the nature of the rpsB1 mutation. Sequencing of the rpsB1 allele revealed a G-to-A transition in the part of the rpsB gene which encodes a coiled-coil domain of S2. The resulting E132K substitution resides in a highly conserved site, TKKE, a so-called N-terminal capping box, at the beginning of the second alpha helix. The protruding coiled-coil domain of S2 is known to provide binding with 16S rRNA in the head of the 30S subunit and, in addition, to interact with a key mRNA binding protein, S1. Molecular dynamics simulations revealed a detrimental impact of the E132K mutation on the coiled-coil structure and thereby on the interactions between S2 and 16S rRNA, providing a clue for the thermosensitivity of the rpsB1 mutant. Using a strain producing a leaderless lacZ transcript from the chromosomal lac promoter, we demonstrated that not only the rpsB1 mutation generating S2/S1-deficient ribosomes but also the rpsA::IS10 mutation leading to partial deficiency in S1 alone increased translation efficiency of the leaderless mRNA by about 10-fold. Moderate overexpression of S1 relieved all these effects and, moreover, suppressed the thermosensitive phenotype of rpsB1, indicating the role of S1 as an extragenic suppressor of the E132K mutation.

    ID:812
  12. Чугунов А.О., Нольде Д.Е., Пыркова Д.В., Полянский А.А., Пентковский В.М., Ефремов Р.Г. (2013). На пути к новым антибиотикам. Суперкомпьютеры 12, 34–36 [+]

    Проблема резистентности бактерий к действию антибиотиков серьезна как никогда, и медицина всеми силами ищет пути к новым бактерицидным веществам, способным сохранять эффективность в течение долгих лет. Современная биофизика поможет ей в этом — наблюдение за молекулой антибиотика, которая «атакует» бактериальную клетку, подскажет ученым, как создать новые вещества, убивающие бактерий и безвредные для человеческого организма. Возможность для такого наблюдения дают суперкомпьютерные расчеты, а также современные физические модели и математические алгоритмы, предназначенные для изучения в вычислительном эксперименте структуры, динамики и функций сложнейших биологических супрамолекулярных систем. Исследователи из Института биоорганической химии РАН, используя ресурсы нового суперкомпьютера, установленного в лаборатории iScalare МФТИ, изучили на атомном уровне особенности организации мембраны бактерий, используя которые антибиотики преодолевают защитные системы клетки и оказывают антимикробное действие. Полученный результат указывает на возможность разработки нового поколения антибиотиков, избавленных от бремени резистентности.

    ID:816
  13. Чугунов А.О., Полянский А.А., Ефремов Р.Г. (2013). Физическая водобоязнь. Природа 1, 24–34 [+]

    Лист лотоса, по которому вода бегает, собравшись в шарики, водоотталкивающие поверхности и защитные составы для обуви, плавающие в бульоне кружки масла — всё это примеры свойства молекул, называемого гидрофобностью. Помимо этого, гидрофобный эффект играет важную биологическую роль: сворачивание и правильная работа белковых молекул, формирование биомембран, распознавание молекулами друг друга также «запрограммированы» с использованием гидрофобных свойств. Интересно, что гидрофобный эффект не сводится к «обычным» физическим взаимодействиям: за ним стоит Второй закон термодинамики и величина, именуемая энтропией.

    ID:817
  14. Polyansky A.A., Chugunov A.O., Vassilevski A.A., Grishin E.V., Efremov R.G. (2012). Recent Advances in Computational Modeling of α-Helical Membrane- Active Peptides. Curr. Protein Pept. Sci. 13 (7), 644–57 [+]

    Membrane-active peptides (MAPs) represent a broad variety of molecules, and biological functions of most are directly associated with their ability to interact with membranes. Taking into account the effect of MAPs on living cells they can be nominally divided into three major groups - fusion (FPs), antimicrobial/cytolytic (AMPs/CPs) and cellpenetrating (CPPs) peptides. Although spatial structure of different MAPs varies to a great extent, linear α-helical peptides represent the most studied class. These peptides possess relatively simple structural organization and share a set of similar molecular features, which make them very attractive to both experimental and computational studies. Here, we review different molecular modeling methods in prospective of their applications to study of α-helical MAPs. The most sophisticated of them, such as molecular dynamics simulations, give atomistic information about molecular interactions driving peptide binding to the water-lipid interface, cooperative mechanisms of membrane destabilization and thermodynamics of these processes. Significant progress has been achieved in this field during the last few years, resulting in a possibility to observe computationally MAPs action in realistic peptide-to-lipid ratios and over the microsecond timescale. Other relatively simple but powerful approaches allow assessment of important characteristics of MAPs such as α-helical propensity, amphiphilicity, total hydrophobicity, and spatial distribution of charge and hydrophobic/hydrophilic properties, etc. Altogether, computational methods provide efficient basis for rational design of MAPs with predefined properties and a spectrum of biological activities.

    ID:813
  15. Чугунов А.О., Полянский А.А., Ефремов Р.Г. (2012). Липидный фундамент жизни. Природа  (3), 3–12 [+]

    Жизнь в том виде, в каком мы ее знаем, невозможно представить без биомембраны, разделяющей «внутренний мир» клетки и всё остальное пространство. Мембрана обеспечивает взаимодействие клетки с внешней средой, избирательно пропуская многие вещества, а также является средой протекания множества биохимических процессов. И хотя большую часть полезной работы выполняют белки, которыми мембрана буквально «нашпигована», роль липидного матрикса не стоит недооценивать. Липиды — это не просто «океан», в котором плавают белки. Это «умный» океан, чьи физико-химические свойства были тщательно подобраны в ходе эволюции так, чтобы создать эффективную платформу для функционирования и взаимодействия мембранных белков.

    ID:747
  16. Semenova A.A., Chugunov A.O., Dubovskii P.V., Chupin V.V., Volynsky P.E., Boldyrev I.A. (2011). The role of chain rigidity in lipid self-association: Comparative study of dihexanoyl- and disorbyl-phosphatidylcholines. Chem. Phys. Lipids 165, 382–386 [+]

    In the course of structure-function investigations of lipids a phosphatidylcholine molecule with short and rigid tails, di-2,4-hexadienoylphosphatidylcholine (DiSorbPC), was synthesized and studied in comparison with its saturated analog, dihexanoylphosphatidylcholine (DHPC). Conjugated double bonds in the acyl chains in DiSorbPC reduce considerably the number of possible conformers of the lipid within an aggregate. This leads to impaired packing of unsaturated acyl chains and thus, to a surprisingly high (115Å(2)) area per molecule for DiSorbPC at the air-water interface and failure to form micelles of regular size and shape. Details on DiSorbPC aggregation and packing provided by a set of experimental techniques combined with molecular dynamics simulations are presented.

    ID:669
  17. Deyev I.E., Sohet F., Vassilenko K.P., Serova O.V., Popova N.V., Zozulya S.A., Burova E.B., Houillier P., Rzhevsky D.I., Berchatova A.A., Murashev A.N., Chugunov A.O., Efremov R.G., Nikolsky N.N., Bertelli E., Eladari D., Petrenko A.G. (2011). Insulin receptor-related receptor as an extracellular alkali sensor. Cell Metab. 13 (6), 679–89 [+]

    The insulin receptor-related receptor (IRR), an orphan receptor tyrosine kinase of the insulin receptor family, can be activated by alkaline media both in vitro and in vivo at pH >7.9. The alkali-sensing property of IRR is conserved in frog, mouse, and human. IRR activation is specific, dose-dependent and quickly reversible and demonstrates positive cooperativity. It also triggers receptor conformational changes and elicits intracellular signaling. The pH sensitivity of IRR is primarily defined by its L1F extracellular domains. IRR is predominantly expressed in organs that come in contact with mildly alkaline media. In particular, IRR is expressed in the cell subsets of the kidney that secrete bicarbonate into urine. Disruption of IRR in mice impairs the renal response to alkali loading attested by development of metabolic alkalosis and decreased urinary bicarbonate excretion in response to this challenge. We therefore postulate that IRR is an alkali sensor that functions in the kidney to manage metabolic bicarbonate excess.

    ID:429
  18. Чугунов А.О., Ефремов Р.Г. (2010). Компьютерные игры в молекулярную биофизику. Природа  (12), 36–43 [+]

    Кконцу XX в. грань между «классическими» науками практически стерлась, исследования стали междисциплинарными. В текущем столетии тенденция усиливается — слияние «обычной» (хотя тоже междисциплинарной!) молекулярной биофизики и того, что называют theoretical computer science, породило необыкновенную область исследований — компьютерный, или in silico, эксперимент. Но прежде чем рассказать о методической подоплеке подхода in silico и о его конкретном использовании для имитационного изучения «жизни» биологических мембран и населяющих их белковых молекул, напомним предысторию.

    ID:746
  19. Chugunov A.O., Simms J., Poyner D.R., Dehouck Y., Rooman M., Gilis D., Langer I. (2010). Evidence that interaction between conserved residues in transmembrane helices 2, 3, and 7 are crucial for human VPAC1 receptor activation. Mol. Pharmacol. 78 (3), 394–401 [+]

    The VPAC(1) receptor belongs to family B of G protein-coupled receptors (GPCR-B) and is activated upon binding of the vasoactive intestinal peptide (VIP). Despite the recent determination of the structure of the N terminus of several members of this receptor family, little is known about the structure of the transmembrane (TM) region and about the molecular mechanisms leading to activation. In the present study, we designed a new structural model of the TM domain and combined it with experimental mutagenesis experiments to investigate the interaction network that governs ligand binding and receptor activation. Our results suggest that this network involves the cluster of residues Arg(188) in TM2, Gln(380) in TM7, and Asn(229) in TM3. This cluster is expected to be altered upon VIP binding, because Arg(188) has been shown previously to interact with Asp(3) of VIP. Several point mutations at positions 188, 229, and 380 were experimentally characterized and were shown to severely affect VIP binding and/or VIP-mediated cAMP production. Double mutants built from reciprocal residue exchanges exhibit strong cooperative or anticooperative effects, thereby indicating the spatial proximity of residues Arg(188), Gln(380), and Asn(229). Because these residues are highly conserved in the GPCR-B family, they can moreover be expected to have a general role in mediating function.

    ID:368
  20. Чугунов А.О., Ефремов Р.Г. (2009). Предсказание пространственной структуры белков: акцент на мембранных мишенях. Биоорг. хим. 35 (6), 1–17 [+]

    Интегральные белки биологических мембран — объекты, пространственная структура которых с большим трудом поддаётся экспериментальному определению. Во многих случаях существует возможность теоретического предсказания строения белковых молекул, используя физические или эмпирические закономерности. В обзоре рассмотрены основные существующие приёмы предсказания пространственной структуры белков с использованием компьютерных алгоритмов; основной акцент сделан на наиболее «сложные» объекты — мембранных белки (МБ).

    Отдельно описаны идеология “de novo”-предсказаний, основывающаяся на эмпирических физических закономерностях, и подход сопоставительного моделирования (или моделирования на основании гомологии), в котором используется информация о трёхмерном строении родственных белков. В качестве примеров рассмотрены фармакологически важные классы G-белоксопряжённых рецепторов, рецепторных тирозинкиназ и другие МБ. Обсуждаются потенциальные сферы применения моделей белков и существующие подходы к оценке «качества» упаковки полипептидной цепи в моделях.

    ID:188
  21. Pyrkov T.V., Chugunov A.O., Krylov N.A., Nolde D.E., Efremov R.G. (2009). PLATINUM: a web tool for analysis of hydrophobic/hydrophilic organization of biomolecular complexes. Bioinformatics 25 (9), 1201–2 [+]

    The PLATINUM (Protein-Ligand ATtractions Investigation NUMerically) web service is designed for analysis and visualization of hydrophobic/hydrophilic properties of biomolecules supplied as 3D-structures. Furthermore, PLATINUM provides a number of tools for quantitative characterization of the hydrophobic/hydrophilic match in biomolecular complexes e.g. in docking poses. These complement standard scoring functions. The calculations are based on the concept of empirical Molecular Hydrophobicity Potential (MHP). AVAILABILITY: The PLATINUM web tool as well as detailed documentation and tutorial are available free of charge for academic users at http://model.nmr.ru/platinum/. PLATINUM requires Java 5 or higher and Adobe Flash Player 9. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

    ID:184
  22. Farce A., Chugunov A.O., Logé C., Sabaouni A., Yous S., Dilly S., Renault N., Vergoten G., Efremov R.G., Lesieur D., Chavatte P. (2008). Homology modeling of MT1 and MT2 receptors. European journal of medicinal chemistry 43 (9), 1926–44 [+]

    Melatonin is a neurohormone synthesized and secreted mainly during the dark period of the circadian cycle by the pineal gland. It has already been proved to be involved in a number of chronobiological processes, most of them being mediated by its membranar receptors MT1 and MT2. Both are members of the GPCR class and, despite the interest they elicit, their 3D structure is still to be described. Models for both human MT1 and MT2 receptors have been constructed by homology modeling, using the X-ray structure of bovine rhodopsin as template. These models have been evaluated in terms of hydrophobic properties of the helices and refined to take into account the rearrangement of GPCRs necessary for their activation, thus leading to a putative activated model for each subtype.

    ID:179
  23. Chugunov A.O., Novoseletsky V.N., Nolde D.E., Arseniev A.S., Efremov R.G. (2007). Method to assess packing quality of transmembrane alpha-helices in proteins. 1. Parametrization using structural data. Journal of chemical information and modeling 47 (3), 1150–62 [+]

    Integral membrane proteins (MPs) are pharmaceutical targets of exceptional importance. Modern methods of three-dimensional protein structure determination often fail to supply the fast growing field of structure-based drug design with the requested MPs' structures. That is why computational modeling techniques gain a special importance for these objects. Among the principal difficulties limiting application of these methods is the low quality of the MPs' models built in silico. In this series of two papers we present a computational approach to the assessment of the packing "quality" of transmembrane (TM) alpha-helical domains in proteins. The method is based on the concept of protein environment classes, whereby each amino acid residue is described in terms of its environment polarity and accessibility to the membrane. In the first paper we analyze a nonredundant set of 26 TM alpha-helical domains and compute the residues' propensities to five predefined classes of membrane-protein environments. Here we evaluate the proposed approach only by various test sets, cross-validation protocols and ability of the method to delimit the crystal structure of visual rhodopsin, and a number of its erroneous theoretical models. More advanced validation of the method is given in the second article of this series. We assume that the developed "membrane score" method will be helpful in optimizing computer models of TM domains of MPs, especially G-protein coupled receptors.

    ID:1
  24. Chugunov A.O., Novoseletsky V.N., Nolde D.E., Arseniev A.S., Efremov R.G. (2007). Method to assess packing quality of transmembrane alpha-helices in proteins. 2. Validation by "correct vs misleading" test. Journal of chemical information and modeling 47 (3), 1163–70 [+]

    We describe a set of tests designed to check the ability of the new "membrane score" method (see the first paper of this series) to assess the packing quality of transmembrane (TM) alpha-helical domains in proteins. The following issues were addressed: (1) Whether there is a relation between the score (S(mem)) of a model and its closeness to the "nativelike" conformation? (2) Is it possible to recognize a correct model among misfolded and erroneous ones? (3) To what extent the score of a homology-built model is sensitive to errors in sequence alignment? To answer the first question, two test cases were considered: (i) Several models of bovine aquaporin-1 (target protein) were built on the structural templates provided by its homologs with known X-ray structure. (ii) Side chains in the spatial models of visual rhodopsin and cytochrome c oxidase were rebuilt based on the backbone scaffolds taken from their crystal structures, and the resulting models were iteratively fitted into the full-atom X-ray conformations. It was shown that the higher the S(mem) value of a model is, the lower its root-mean-square deviation is from the "correct" (crystal) structure of a target. Furthermore, the "membrane score" method successfully identifies the rhodopsin crystal structure in an ensemble of "rotamer-type" decoys, thus providing the way to optimize mutual orientations of alpha-helices in models of TM domains. Finally, being applied to a set of homology models of rhodopsin built on its crystal structure with systematically shifted alignment, the approach demonstrates a prominent ability to detect alignment errors. We therefore assume that the "membrane score" method will be helpful in optimization of in silico models of TM domains in proteins, especially those in GPCRs.

    ID:2
  25. Chugunov A.O., Novoseletsky V.N., Arseniev A.S., Efremov R.G. (2007). A novel method for packing quality assessment of transmembrane alpha-helical domains in proteins. Biochemistry Mosc. 72 (3), 293–300 [+]

    Here we present a novel method for assessment of packing quality for transmembrane (TM) domains of alpha-helical membrane proteins (MPs), based on analysis of available high-resolution experimental structures of MPs. The presented concept of protein-membrane environment classes permits quantitative description of packing characteristics in terms of membrane accessibility and polarity of the nearest protein groups. We demonstrate that the method allows identification of native-like conformations among the large set of theoretical MP models. The developed "membrane scoring function" will be of use for optimization of TM domain packing in theoretical models of MPs, first of all G-protein coupled receptors.

    ID:186
  26. Efremov R.G., Chugunov A.O., Pyrkov T.V., Priestle J.P., Arseniev A.S., Jacoby E. (2007). Molecular lipophilicity in protein modeling and drug design. Curr. Med. Chem. 14 (4), 393–415 [+]

    Hydrophobic interactions play a key role in the folding and maintenance of the 3-dimensional structure of proteins, as well as in the binding of ligands (e.g. drugs) to protein targets. Therefore, quantitative assessment of spatial hydrophobic (lipophilic) properties of these molecules is indispensable for the development of efficient computational methods in drug design. One possible solution to the problem lies in application of a concept of the 3-dimensional molecular hydrophobicity potential (MHP). The formalism of MHP utilizes a set of atomic physicochemical parameters evaluated from octanol-water partition coefficients (log P) of numerous chemical compounds. It permits detailed assessment of the hydrophobic and/or hydrophilic properties of various parts of molecules and may be useful in analysis of protein-protein and protein-ligand interactions. This review surveys recent applications of MHP-based techniques to a number of biologically relevant tasks. Among them are: (i) Detailed assessment of hydrophobic/hydrophilic organization of proteins; (ii) Application of this data to the modeling of structure, dynamics, and function of globular and membrane proteins, membrane-active peptides, etc. (iii) Employment of the MHP-based criteria in docking simulations for ligands binding to receptors. It is demonstrated that the application of the MHP-based techniques in combination with other molecular modeling tools (e.g. Monte Carlo and molecular dynamics simulations, docking, etc.) permits significant improvement to the standard computational approaches, provides additional important insights into the intimate molecular mechanisms driving protein assembling in water and in biological membranes, and helps in the computer-aided drug discovery process.

    ID:185
  27. Chugunov A.O., Farce A., Chavatte P., Efremov R.G. (2006). Differences in binding sites of two melatonin receptors help to explain their selectivity to some melatonin analogs: a molecular modeling study. J. Biomol. Struct. Dyn. 24 (2), 91–107 [+]

    Numerous diseases have been linked to the malfunction of G-protein coupled receptors (GPCRs). Their adequate treatment requires rational design of new high-affinity and high-selectivity drugs targeting these receptors. In this work, we report three-dimensional models of the human MT(1) and MT(2) melatonin receptors, members of the GPCR family. The models are based on the X-ray structure of bovine rhodopsin. The computational approach employs an original procedure for optimization of receptor-ligand structures. It includes rotation of one of the transmembrane alpha-helices around its axis with simultaneous assessment of quality of the resulting complexes according to a number of criteria we have developed for this purpose. The optimal geometry of the receptor-ligand binding is selected based on the analysis of complementarity of hydrophobic/hydrophilic properties between the ligand and its protein environment in the binding site. The elaborated "optimized" models are employed to explore the details of protein-ligand interactions for melatonin and a number of its analogs with known affinity to MT(1) and MT(2) receptors. The models permit rationalization of experimental data, including those that were not used in model building. The perspectives opened by the constructed models and by the optimization procedure in the design of new drugs are discussed.

    ID:187