Anton A. Polyansky


PeriodCountry, cityEducation institutionAdditional info
1998–2003 Russia, Moscow Dept. of Biophysics, Faculty of Biological Sciences M.V. Lomonosov State University with honor

Scientific interests

My major interests are: 1) organization of biomolecular surfaces, 2) principles of polypeptide chain folding in different environments (water, water-lipid interface, membrane etc.), 3) mechanisms of protein oligomerization in the membrane medium, 4) protein-membrane and protein-RNA interactions, and 5) design of novel drugs, which have specific membrane targets.

In my research I use combined molecular modeling approaches. Among them are:

  • coarse-grained and atomistic computer simulations of proteins, peptides and drugs in explicit solvents and membrane systems (molecular dynamics, free energy estimation etc.);
  • molecular hydrophobicity potential calculations and surface analysis of biomolecules;
  • bioinformatics analysis of protein and RNA sequences.




Selected publications

  1. Zhang L., Polyansky A., Buck M. (2015). Modeling transmembrane domain dimers/trimers of plexin receptors: implications for mechanisms of signal transmission across the membrane. PLoS ONE 10 (4), e0121513 [+]

    Single-pass transmembrane (TM) receptors transmit signals across lipid bilayers by helix association or by configurational changes within preformed dimers. The structure determination for such TM regions is challenging and has mostly been accomplished by NMR spectroscopy. Recently, the computational prediction of TM dimer structures is becoming recognized for providing models, including alternate conformational states, which are important for receptor regulation. Here we pursued a strategy to predict helix oligomers that is based on packing considerations (using the PREDDIMER webserver) and is followed by a refinement of structures, utilizing microsecond all-atom molecular dynamics simulations. We applied this method to plexin TM receptors, a family of 9 human proteins, involved in the regulation of cell guidance and motility. The predicted models show that, overall, the preferences identified by PREDDIMER are preserved in the unrestrained simulations and that TM structures are likely to be diverse across the plexin family. Plexin-B1 and -B3 TM helices are regular and tend to associate, whereas plexin-A1, -A2, -A3, -A4, -C1 and -D1 contain sequence elements, such as poly-Glycine or aromatic residues that distort helix conformation and association. Plexin-B2 does not form stable dimers due to the presence of TM prolines. No experimental structural information on the TM region is available for these proteins, except for plexin-C1 dimeric and plexin-B1 - trimeric structures inferred from X-ray crystal structures of the intracellular regions. Plexin-B1 TM trimers utilize Ser and Thr sidechains for interhelical contacts. We also modeled the juxta-membrane (JM) region of plexin-C1 and plexin-B1 and show that it synergizes with the TM structures. The structure and dynamics of the JM region and TM-JM junction provide determinants for the distance and distribution of the intracellular domains, and for their binding partners relative to the membrane. The structures suggest experimental tests and will be useful for the interpretation of future studies.

  2. Ribeiro Ede.A. Jr, Pinotsis N., Ghisleni A., Salmazo A., Konarev P.V., Kostan J., Sjöblom B., Schreiner C., Polyansky A.A., Gkougkoulia E.A., Holt M.R., Aachmann F.L., Zagrovic B., Bordignon E., Pirker K.F., Svergun D.I., Gautel M., DjinovićCarugo K. (2014). The Structure and Regulation of Human Muscle α-Actinin. Cell 159 (6), 1447–60 [+]

    The spectrin superfamily of proteins plays key roles in assembling the actin cytoskeleton in various cell types, crosslinks actin filaments, and acts as scaffolds for the assembly of large protein complexes involved in structural integrity and mechanosensation, as well as cell signaling. α-actinins in particular are the major actin crosslinkers in muscle Z-disks, focal adhesions, and actin stress fibers. We report a complete high-resolution structure of the 200 kDa α-actinin-2 dimer from striated muscle and explore its functional implications on the biochemical and cellular level. The structure provides insight into the phosphoinositide-based mechanism controlling its interaction with sarcomeric proteins such as titin, lays a foundation for studying the impact of pathogenic mutations at molecular resolution, and is likely to be broadly relevant for the regulation of spectrin-like proteins.

  3. 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.

  4. Peter B., Polyansky A.A., Fanucchi S., Dirr H.W. (2014). A Lys-Trp cation-π interaction mediates the dimerization and function of the chloride intracellular channel protein 1 transmembrane domain. Biochemistry 53 (1), 57–67 [+]

    Chloride intracellular channel protein 1 (CLIC1) is a dual-state protein that can exist either as a soluble monomer or in an integral membrane form. The oligomerization of the transmembrane domain (TMD) remains speculative despite it being implicated in pore formation. The extent to which electrostatic and van der Waals interactions drive folding and association of the dimorphic TMD is unknown and is complicated by the requirement of interactions favorable in both aqueous and membrane environments. Here we report a putative Lys37-Trp35 cation-π interaction and show that it stabilizes the dimeric form of the CLIC1 TMD in membranes. A synthetic 30-mer peptide comprising a K37M TMD mutant was examined in 2,2,2-trifluoroethanol, sodium dodecyl sulfate micelles, and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine liposomes using far-ultraviolet (UV) circular dichroism, fluorescence, and UV absorbance spectroscopy. Our data suggest that Lys37 is not implicated in the folding, stability, or membrane insertion of the TMD peptide. However, removal of this residue impairs the formation of dimers and higher-order oligomers. This is accompanied by a 30-fold loss of chloride influx activity, suggesting that dimerization modulates the rate of chloride conductance. We propose that, within membranes, individual TMD helices associate via a Lys37-mediated cation-π interaction to form active dimers. The latter findings are also supported by results of modeling a putative TMD dimer conformation in which Lys37 and Trp35 form cation-π pairs at the dimer interface. Dimeric helix bundles may then associate to form fully active ion channels. Thus, within a membrane-like environment, aromatic interactions involving a polar lysine side chain provide a thermodynamic driving force for helix-helix association.

  5. 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.

  6. Volynsky P.E., Polyansky A.A., Fakhrutdinova G.N., Bocharov E.V., Efremov R.G. (2013). Role of Dimerization Efficiency of Transmembrane Domains in Activation of Fibroblast Growth Factor Receptor 3. J. Am. Chem. Soc. , [+]

    Mutations in transmembrane (TM) domains of receptor tyrosine kinases are shown to cause a number of inherited diseases and cancer development. Here, we use a combined molecular modeling approach to understand molecular mechanism of effect of G380R and A391E mutations on dimerization of TM domains of human fibroblast growth factor receptor 3 (FGFR3). According to results of Monte Carlo conformational search in the implicit membrane and further molecular dynamics simulations, TM dimer of this receptor is able to form a number of various conformations, which differ significantly by the free energy of association in a full-atom model bilayer. The aforementioned mutations affect dimerization efficiency of TM segments and lead to repopulation of conformational ensemble for the dimer. Particularly, both mutations do not change the dimerization free energy of the predominant (putative "non-active") symmetric conformation of TM dimer, while affect dimerization efficiency of its asymmetric ("intermediate") and alternative symmetric (putative "active") models. Results of our simulations provide novel atomistic prospective of the role of G380 and A391E mutations in dimerization of TM domains of FGFR3 and their consecutive contributions to the activation pathway of the receptor.

  7. 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.

  8. Polyansky A.A., Kuzmanic A., Hlevnjak M., Zagrovic B. (2012). On the Contribution of Linear Correlations to Quasi-harmonic Conformational Entropy in Proteins. J. Chem. Theory Comput. 8, 3820–3829 ID:847
  9. Polyansky A.A., Volynsky P.E., Efremov R.G. (2012). Multistate organization of transmembrane helical protein dimers governed by the host membrane. J. Am. Chem. Soc. 134 (35), 14390–400 [+]

    Association of transmembrane (TM) helices taking place in the cell membrane has an important contribution to the biological function of bitopic proteins, among which receptor tyrosine kinases represent a typical example and a potent target for medical applications. Since this process depends on a complex interplay of different factors (primary structures of TM domains and juxtamembrane regions, composition and phase of the local membrane environment, etc.), it is still far from being fully understood. Here, we present a computational modeling framework, which we have applied to systematically analyze dimerization of 18 TM helical homo- and heterodimers of different bitopic proteins, including the family of epidermal growth factor receptors (ErbBs). For this purpose, we have developed a novel surface-based modeling approach, which not only is able to predict particular conformations of TM dimers in good agreement with experiment but also provides screening of their conformational heterogeneity. Using all-atom molecular dynamics simulations of several of the predicted dimers in different model membranes, we have elucidated a putative role of the environment in selection of particular conformations. Simulation results clearly show that each particular bilayer preferentially stabilizes one of possible dimer conformations, and that the energy gain depends on the interplay between structural properties of the protein and the membrane. Moreover, the character of protein-driven perturbations of the bilayer is reflected in the contribution of a particular membrane to the free energy gain. We have found that the approximated dimerization strength for ErbBs family can be related to their oncogenic ability.

  10. Polyansky A.A., Zagrovic B. (2012). Protein Electrostatic Properties Predefining the Level of Surface Hydrophobicity Change upon Phosphorylation. J Phys Chem Lett 3, 973–976 [+]

    We use explicit-solvent, molecular dynamics simulations to study the change in polar properties of a solvent-accessible surface for proteins undergoing phosphorylation. We analyze eight different pairs of proteins representing different structural classes in native and phosphorylated states and estimate the polarity of their surface using the molecular hydrophobicity potential approach. Whereas the phosphorylation-induced hydrophobicity change in the vicinity of phosphosites does not vary strongly among the studied proteins, the equivalent change for complete proteins covers a surprisingly wide range of effects including even an increase in the overall hydrophobicity in some cases. Importantly, the observed changes are strongly related to electrostatic properties of proteins, such as the net charge per residue, the distribution of charged side-chain contacts, and the isoelectric point. These features predefine the level of surface hydrophobicity change upon phosphorylation and may thus contribute to the phosphorylation-induced alteration of the interactions between a protein and its environment.

  11. Polyansky A.A., Zubac R., Zagrovic B. (2012). Estimation of conformational entropy in protein-ligand interactions: a computational perspective. Methods Mol. Biol. 819, 327–53 [+]

    Conformational entropy is an important component of the change in free energy upon binding of a ligand to its target protein. As a consequence, development of computational techniques for reliable estimation of conformational entropies is currently receiving an increased level of attention in the context of computational drug design. Here, we review the most commonly used techniques for conformational entropy estimation from classical molecular dynamics simulations. Although by-and-large still not directly used in practical drug design, these techniques provide a golden standard for developing other, computationally less-demanding methods for such applications, in addition to furthering our understanding of protein-ligand interactions in general. In particular, we focus on the quasi-harmonic approximation and discuss different approaches that can be used to go beyond it, most notably, when it comes to treating anharmonic and/or correlated motions. In addition to reviewing basic theoretical formalisms, we provide a concrete set of steps required to successfully calculate conformational entropy from molecular dynamics simulations, as well as discuss a number of practical issues that may arise in such calculations.

  12. Polyansky A.A., Volynsky P.E., Efremov R.G. (2011). Structural, dynamic, and functional aspects of helix association in membranes: a computational view. Adv Protein Chem Struct Biol 83, 129–61 [+]

    This review surveys recent achievements of molecular computer modeling in understanding spatial structure, dynamics, and mechanisms of functioning of transmembrane α-helical dimers in membranes. The factors driving self-association of hydrophobic helices in the membrane milieu are considered with examples of their applications to biologically relevant problems. The emphasis is made on the recent results, which help to understand important aspects of structure-function relations for these systems and their biological activity. Limitations and shortcomings of the methods, along with their perspectives in design of new membrane active agents, are discussed.

  13. Polyansky A.A., Ramaswamy R., Volynsky P.E., Sbalzarini I.F., Marrink S.J., Efremov R.G. (2010). Antimicrobial Peptides Induce Growth of Phosphatidylglycerol Domains in a Model Bacterial Membrane. J. Phys. Chem. Lett. 1, 3108–3111 [+]

    We performed microsecond long coarse-grained molecular dynamics simulations to elucidate the lateral structure and domain dynamics of a phosphatidylethanolamine (PE)/phosphatidylglycerol (PG) mixed bilayer (7/3), mimicking the inner membrane of gram-negative bacteria. Specifically, we address the effect of surface bound antimicrobial peptides (AMPs) on the lateral organization of the membrane. We find that, in the absence of the peptides, the minor PG fraction only forms small clusters, but that these clusters grow in size upon binding of the cationic AMPs. The presence of AMPs systematically affects the dynamics and induces long-range order in the structure of PG domains, stabilizing the separation between the two lipid fractions. Our results help in understanding the initial stages of destabilization of cytoplasmic bacterial membranes below the critical peptide concentration necessary for disruption, and provide a possible explanation for the multimodal character of AMP activity.

  14. Polyansky A.A., Vassilevski A.A., Volynsky P.E., Vorontsova O.V., Samsonova O.V., Egorova N.S., Krylov N.A., Feofanov A.V., Arseniev A.S., Grishin E.V., Efremov R.G. (2009). N-terminal amphipathic helix as a trigger of hemolytic activity in antimicrobial peptides: a case study in latarcins. FEBS Lett. 583 (14), 2425–8 [+]

    In silico structural analyses of sets of alpha-helical antimicrobial peptides (AMPs) are performed. Differences between hemolytic and non-hemolytic AMPs are revealed in organization of their N-terminal region. A parameter related to hydrophobicity of the N-terminal part is proposed as a measure of the peptide propensity to exhibit hemolytic and other unwanted cytotoxic activities. Based on the information acquired, a rational approach for selective removal of these properties in AMPs is suggested. A proof of concept is gained through engineering specific mutations that resulted in elimination of the hemolytic activity of AMPs (latarcins) while leaving the beneficial antimicrobial effect intact.

  15. Polyansky A.A., Volynsky P.E., Arseniev A.S., Efremov R.G. (2009). Adaptation of a membrane-active peptide to heterogeneous environment. I. Structural plasticity of the peptide. The journal of physical chemistry. B 113 (4), 1107–19 [+]

    A detailed study of different factors determining interaction of a membrane-active peptide (a cell-penetrating peptide — penetratin) is presented. It concerns the role of conformational plasticity of the peptide in different membrane environment, as well as the ability of the peptide to form stable specific residue-residue interactions and make contacts with particular lipids.

  16. Polyansky A.A., Volynsky P.E., Arseniev A.S., Efremov R.G. (2009). Adaptation of a membrane-active peptide to heterogeneous environment. II. The role of mosaic nature of the membrane surface. The journal of physical chemistry. B 113 (4), 1120–6 [+]

    This study postulates the mosaic hydrophobic-hydrophilic organization of the lipid membrane surface. Special attention is given to the influence of such heterogeneous polar properties of the water-lipid interface on the binding mode of membrane-active agents (a case study of cell-penetrating peptide — penetratin).

  17. Polyansky A.A., Volynsky P.E., Nolde D.E., Arseniev A.S., Efremov R.G. (2005). Role of lipid charge in organization of water/lipid bilayer interface: insights via computer simulations. The journal of physical chemistry. B 109 (31), 15052–9 [+]

    Anionic unsaturated lipid bilayers represent suitable model systems that mimic real cell membranes: they are fluid and possess a negative surface charge. Understanding of detailed molecular organization of water-lipid interfaces in such systems may provide an important insight into the mechanisms of proteins' binding to membranes. Molecular dynamics (MD) of full-atom hydrated lipid bilayers is one of the most powerful tools to address this problem in silico. Unfortunately, wide application of computational methods for such systems is limited by serious technical problems. They are mainly related to correct treatment of long-range electrostatic effects. In this study a physically reliable model of an anionic unsaturated bilayer of 1,2-dioleoyl-sn-glycero-3-phosphoserine (DOPS) was elaborated and subjected to long-term MD simulations. Electrostatic interactions were treated with two different algorithms: spherical cutoff function and particle-mesh Ewald summation (PME). To understand the role of lipid charge in the system behavior, similar calculations were also carried out for zwitterionic bilayer composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). It was shown that, for the charged DOPS bilayer, the PME protocol performs much better than the cutoff scheme. In the last case a number of artifacts in the structural organization of the bilayer were observed. All of them were attributed to inadequate treatment of electrostatic interactions of lipid headgroups with counterions. Electrostatic properties, along with structural and dynamic parameters, of both lipid bilayers were investigated. Comparative analysis of the MD data reveals that the water-lipid interface of the DOPC bilayer is looser than that for DOPS. This makes possible deeper penetration of water molecules inside the zwitterionic (DOPC) bilayer, where they strongly interact with carbonyls of lipids. This can lead to thickening of the membrane interface in zwitterionic as compared to negatively charged bilayers.