-
P. E. Volynsky,
E. V. Bocharov,
D. E. Nolde,
Ya. A. Vereschaga,
M. L. Mayzel,
K. S. Mineev,
E. A. Mineeva,
Yu. E. Pustovalova,
I. A. Gagnidze, R. G. Efremov,
A. S. Arseniev
[show abstract]
[hide abstract]
ABSTRACT: Membrane proteins play an important role in various biological processes. An approach combining NMR spectroscopy with molecular
modeling was used to study the spatial structure and intramolecular dynamics of protein transmembrane domains consisting of
two interacting α-helices. The approach was tested with model transmembrane domains and yielded detailed atomic-level data
on the protein-protein and protein-lipid interactions.
Biophysics 05/2012; 51:23-27.
-
[show abstract]
[hide abstract]
ABSTRACT: Investigation of lateral heterogeneities (clusters) in cell membranes is an important step toward understanding the physical
processes that lead to the formation of lipid domains and rafts. Computer modeling methods represent a powerful tool to solve
the problem, since they can detect clusters containing only a few lipid molecules—the situation that still resists characterization
with modern experimental techniques. Parameters of clustering depend on lipid composition of a membrane. In this work, we
propose a computational method to detect and analyze parts of membrane with different packing densities. Series of one- and
two-component fluid systems containing lipids with the same polar heads and different acyl chains, dioleoylphosphatidylcholine
(18 : 1) and dipalmitoylphosphatidylcholine (16 : 0), were chosen as the objects under study. The developed algorithm is based
on molecular dynamics simulation of hydrated lipid bilayers in all-atom mode. The method is universal and could be applied
to any other membrane system with arbitrary lipid composition. Here, we demonstrated that the studied lipid bilayers reveal
small lateral dynamic clusters composed of just several (most often, three) lipid molecules. This seems to be one of the most
important reasons determining the “mosaic” nature of the membrane-water interface.
Keywordslipid membranes–two-component lipid bilayers–molecular dynamics–lateral membrane heterogeneities–lipid-lipid interactions–structural organization of lipid bilayer
Biochemistry (Moscow) Supplement Series A Membrane and Cell Biology 05/2012; 5(3):278-285.
-
[show abstract]
[hide abstract]
ABSTRACT: The conformational space of a hydrophobic peptide fragment of glycophorin A in a lipid membrane was studied with the Monte
Carlo method using the solvation model described in the first communication of this series. The simulation was performed for
various starting orientations of the peptide relative the membrane bilayer: outside, inside, partially immersed, and transbilayer.
We showed that the membrane substantially stabilizes the α-helical conformation of the central hydrophobic part of the glycophorin
A molecule, which for the most part is immersed in the apolar core of the bilayer. For various conformational states, energy
values were calculated and the orientations of the peptide relative to the membrane were characterized. Depending on the thickness
of the bilayer, either an entirely α-helical conformation in transbilayer orientation or a conformation with a kink in the
central part of the helix with theN- andC-termini exposed on one side of the membrane corresponds to the minimal-energy structure. The transmembrane orientation of
glycophorin A is energetically advantageous when the membrane thickness is close to the length of its hydrophobic helical
portion, which is consistent with the effect ofhydrophobic match observed experimentally. The prospects for further refinement of the model are discussed.
Russian Journal of Bioorganic Chemistry 04/2012; 26(3):143-151. · 0.64 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Knowledge of the spatial structure of complexes formed by cellular proteins and membrane receptors with their respective ligands Knowledge of the spatial structure of complexes formed by cellular proteins and membrane receptors with their respective ligands
is an important step towards understanding the mechanisms of their functioning. Rational drug design and the search for new is an important step towards understanding the mechanisms of their functioning. Rational drug design and the search for new
therapeutically active compounds also require structural information on the interaction of prototypic drugs with the target therapeutically active compounds also require structural information on the interaction of prototypic drugs with the target
protein. The present review briefly describes the main computational methods of molecular docking that are used to predict protein. The present review briefly describes the main computational methods of molecular docking that are used to predict
the conformation of a ligand bound to the active center of a protein. Approaches enabling an increase of the precision and the conformation of a ligand bound to the active center of a protein. Approaches enabling an increase of the precision and
efficiency of the currently used docking algorithms are exemplified by the recent projects of the Laboratory of Biomolecular efficiency of the currently used docking algorithms are exemplified by the recent projects of the Laboratory of Biomolecular
Modeling of IBCh RAS. Special attention is paid to hydrophilic and hydrophobic interactions, as well as to the stacking phenomena Modeling of IBCh RAS. Special attention is paid to hydrophilic and hydrophobic interactions, as well as to the stacking phenomena
that account for the molecular recognition of specific ligand fragments. These types of contacts are often inadequately describedtypes of contacts are often inadequately described
by the algorithms of the estimation of the intermolecular interaction energy of the existing docking programs (scoring functions), by the algorithms of the estimation of the intermolecular interaction energy of the existing docking programs (scoring functions),
this ultimately leading to erroneous predictions of the three-dimensional structure of complexes. Therefore, a thorough consideration this ultimately leading to erroneous predictions of the three-dimensional structure of complexes. Therefore, a thorough consideration
of these interactions is one of the most important tasks of molecular modeling. of these interactions is one of the most important tasks of molecular modeling.
Key wordsdocking scoring function-hydrogen bonds-hydrophobic interactions-stacking Key wordsdocking scoring function-hydrogen bonds-hydrophobic interactions-stacking
Russian Journal of Bioorganic Chemistry 04/2012; 36(4):446-455. · 0.64 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A theoretical solvation model of peptides and proteins that mimics the heterogeneous membrane-water system was proposed. Our
approach is based on the combined use of atomic parameters of solvation for water and hydrocarbons, which approximates the
hydrated polar groups and acyl chains of lipids, respectively. This model was tested in simulations of several peptides: a
nonpolar 20-mer polyleucine, a hydrophobic peptide with terminal polar groups, and a strongly amphiphilic peptide. The conformational
space of the peptides in the presence of the membrane was studied by the Monte Carlo method. Unlike a polar solvent and vacuum,
the membrane-like environment was shown to stabilize the α-helical conformation: low-energy structures have a helicity index
of 100% in all cases. At the same time, the energetically most favorable orientations of the peptides relative to the membrane
depend on their hydrophobic properties: nonpolar polyleucine is entirely immersed in the bilayer and the hydrophobic peptide
with polar groups at the termini adopts a transbilayer orientation, whereas the amphiphilic peptide lies at the interface
parallel to the membrane plane. The results of the simulations agree well with the available experimental data for these systems.
In the following communications of this series, we plan to describe applications of the solvation model to membrane-bound
proteins and peptides with biologically important functional activities.
Russian Journal of Bioorganic Chemistry 04/2012; 26(2):115-124. · 0.64 Impact Factor
-
K S Mineev,
E V Bocharov,
P E Volynsky,
M V Goncharuk,
E N Tkach,
Ya S Ermolyuk,
A A Schulga,
V V Chupin,
I V Maslennikov, R G Efremov,
A S Arseniev
[show abstract]
[hide abstract]
ABSTRACT: Specific interactions between transmembrane α-helices, to a large extent, determine the biological function of integral membrane proteins upon normal development and in pathological states of an organism. Various membrane-like media, partially those mimicking the conditions of multicomponent biological membranes, are used to study the structural and thermodynamic features that define the character of oligomerization of transmembrane helical segments. The choice of the composition of the membrane-mimicking medium is conducted in an effort to obtain a biologically relevant conformation of the protein complex and a sample that would be stable enough to allow to perform a series of long-term experiments with its use. In the present work, heteronuclear NMR spectroscopy and molecular dynamics simulations were used to demonstrate that the two most widely used media (detergent DPC micelles and lipid DMPC/DHPC bicelles) enable to perform structural studies of the specific interactions between transmembrane α-helices by the example of dimerizing the transmembrane domain of the bitopic protein glycophorin A. However, a number of peculiarities place lipid bicelles closer to natural lipid bilayers in terms of their physical properties.
Acta naturae. 04/2011; 3(2):90-8.
-
[show abstract]
[hide abstract]
ABSTRACT: The cytotoxic properties of cytotoxins (CTs) from snake venom are mediated by their interaction with the cell membrane. The hydrophobic pattern containing the tips of loops I-III and flanked by polar residues is known to be a membrane-binding motif of CTs. However, this is not enough to explain the difference in activity among various CTs which are similar in sequence and in 3D structure. The mechanism of further CT-membrane interaction leading to pore formation and cell death still remains unknown. Published experimental data on the specific interaction between CT and low molecular weight anionic components (sulphatide) of the bilayer point to the existence of corresponding ligand binding sites on the surface of toxin molecules. In this work we study the membrane-lytic properties of CT I, CT II (Naja oxiana), and Ct 4 (Naja kaouthia), which belong to different structural and functional types (P- and S-type) of CTs, by measuring the intensity of a fluorescent dye, calcein released from liposomes containing a phosphatidylserine (PS) lipid as an anionic component. Using molecular docking simulations, we find and characterize three sites in CT molecules that can potentially bind the PS polar head. Based on the data obtained, we suggest a hypothesis that CTs can specifically interact with one or more of the anionic lipids (in particular, with PS) contained in the membrane, thus facilitating the interaction between CTs and the lipid bilayer of a cell membrane.
Acta naturae. 07/2010; 2(2):88-96.
-
[show abstract]
[hide abstract]
ABSTRACT: Membrane-spanning segments of numerous proteins (e.g. receptor tyrosine kinases) represent a novel class of pharmacologically important targets, whose activity can be modulated by specially designed artificial peptides, the so-called interceptors. Rational construction of such peptides requires understanding of the main factors driving peptide-peptide association in lipid membranes. Here we present a new method for rapid prediction of the spatial structure of transmembrane (TM) helix-helix complexes. It is based on computer simulations in membrane-like media and subsequent refinement/validation of the results using experimental studies of TM helix dimerization in a bacterial membrane by means of the ToxR system. The approach was applied to TM fragments of the ephrin receptor A1 (EphA1). A set of spatial structures of the dimer was proposed based on Monte Carlo simulations in an implicit membrane followed by molecular dynamics relaxation in an explicit lipid bilayer. The resulting models were employed for rational design of wild-type and mutant genetic constructions for ToxR assays. The computational and the experimental data are self-consistent and provide an unambiguous spatial model of the TM dimer of EphA1. The results of this work can be further used to develop new biologically active 'peptide interceptors' specifically targeting membrane domains of proteins.
Physical Biology 01/2010; 7:16014. · 2.60 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The adrenergic receptors mediate a wide variety of physiological responses, including vasodilatation and vasoconstriction, heart rate modulation, and others. Beta-adrenergic antagonists ('beta-blockers') thus constitute a widely used class of drugs in cardiovascular medicine as well as in management of anxiety, migraine, and glaucoma. The importance of the hydrophobic effect has been evidenced for a wide range of beta-blocker properties. To better understand the role of the hydrophobic effect in recognition of beta-blockers by their receptor, we carried out a molecular docking study combined with an original approach to estimate receptor-ligand hydrophobic interactions. The proposed method is based on automatic detection of molecular fragments in ligands and the analysis of their interactions with receptors separately. A series of beta-blockers, based on phenylethanolamines and phenoxypropanolamines, were docked to the beta2-adrenoceptor binding site in the crystal structure. Hydrophobic complementarity between the ligand and the receptor was calculated using the PLATINUM web-server (http://model.nmr.ru/platinum). Based on the analysis of the hydrophobic match for molecular fragments of beta-blockers, we have developed a new scoring function which efficiently predicts dissociation constant (pKd) with strong correlations (r(2) approximately 0.8) with experimental data.
SAR and QSAR in environmental research 01/2010; 21(1):37-55. · 1.68 Impact Factor
-
Acta naturae. 04/2009; 1(1):124-7.
-
[show abstract]
[hide abstract]
ABSTRACT: Work on surface-enhanced Raman scattering (RS) of light by molecules near a metal surface is reviewed. The experimental conditions for obtaining surface-enhanced Raman scattering spectra in different molecule-metal systems are examined. The basic characteristics and mechanisms of the effect are discussed. Special attention is devoted to applications of the method of surface-enhanced Raman scattering spectroscopy for structural-functional study of biological molecules: DNA, proteins, supramolecular complexes. It is pointed out that the large enhancement of the RS cross section makes it possible to reduce the concentration of the substances under study by three orders of magnitude—down to 10−8–10−9 M. The short range of the enhancement mechanism in some systems makes it possible to obtain Raman scattering spectra for groups of atoms located directly adjacent to the surface of the metal and thereby to study the topography of biological macromolecules and the kinetics of their behavior at an interface. The prospects for applications of enhanced Raman scattering as a new method of vibrational spectroscopy of biopolymers are discussed.
Soviet Physics Uspekhi 10/2007; 31(3):241.
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
Biochemistry (Moscow) 04/2007; 72(3):293-300. · 1.06 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Surface enhanced Raman (SER) spectra of bacteriorhodopsin (BRh) in the purple membranes of Halobacterium halobium, rhodopsin (Rh) in the photoreceptor dises of rod outer segments and complexes of Rh with monoclonal antibodies and photoreceptor dises closed with the cytoplasmic surface inwards were analysed. After adsorption of the membrane proteins on silver electrodes treated via an oxidation-reduction cycle (ORC) and on unaggregated silver hydrosols with a mean particle diameter about 15 nm, the short-range enhancement mechanisms was shown; it may be used to study the topography of the membrane-bound complexes. In this case adsorption prevents photoinduced conformational transitions of the pigments. If the BRh or Rh molecules are adsorbed on partially aggregated hydrosols with a characteristic particle size aout 100 nm or on “smooth” (i.e. not roughened by the ORC) electrodes, the SERS mechanism has a longer range character. Hence it is possible to detect SER spectra which are similar to those obtained in solution but at concentrations two to three orders of magnitude lower. Under such conditions adsorption does not influence photochemical transformations of bacterial and visual rhodopsins. The potential variation on the “smooth” electrode near the zero charge for silver is accompanied by accumulation of K610, the kinetic intermediate of the BRh photocycle. At the same time, the content of the main form, BRh570, decreases.
Journal of Raman Spectroscopy 04/2005; 21(1):49 - 53. · 3.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The influence of environmental hydrophobicity on the UV resonance Raman spectra of tryptophan residues in proteins was studied using laser excitation at 230 nm. An increase in hydrophobicity was found to enhance the resonance Raman cross-sections without significant changes in the frequencies and relative intensities of the Trp vibrational modes. It was shown that this effect is strong enough to be used for studies of the tryptophanyl micro-environment in proteins. The resonance Raman cross-section of tryptophanyl increases relative to that of N-Ac-Trpethyl ester by factors of 2, 3, 3, 4.4 and 1.6 for melittin, melittin incorporated into liposomes, azurin, bacteriorhodopsin and lysozyme, respectively.
Journal of Raman Spectroscopy 04/2005; 23(2):69 - 73. · 3.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Membrane and membrane-active peptides and proteins play a crucial role in numerous cell processes, such as signaling, ion conductance, fusion, and others. Many of them act as highly specific and efficient drugs or drug targets, and, therefore, attract growing interest of medicinal chemists. Because of experimental difficulties with characterization of their spatial structure and mode of membrane binding, essential attention is given now to molecular modeling techniques. During the last years an important progress has been achieved in molecular dynamics (MD) and Monte Carlo (MC) simulations of peptides and proteins with explicit and/or implicit theoretical models of membranes. The first ones allow atomic-resolution studies of peptides behavior on the membrane-water interfaces. Models with implicit consideration of membrane are of a special interest because of their computational efficiency and ability to account for principal trends in protein-lipid interactions. In this approximation, the bilayer is usually treated as continuum whose properties vary along the membrane thickness, and membrane insertion is simulated using either MC or MD methods. This review surveys recent applications of both types of lipid bilayer models in computer simulations of a wide variety of peptides and proteins with different biological activities. Theoretical background of the membrane models is considered with examples of their applications to biologically relevant problems. The emphasis of the review is made on recent MC and MD computations, on structural and/or functional information, which may be obtained via molecular modeling. The approximations and shortcomings of the models, along with their perspectives in design of new membrane active drugs, are discussed.
Current Medicinal Chemistry 10/2004; 11(18):2421-42. · 4.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: For the development of a method capable of predicting single point mutations substantially affecting protein thermostability, we studied the effect of the E85R and R82E mutations on the thermostability of thioredoxins from Escherichia coli (Trx) andBacillus acidocaldarius (BacTrx), respectively. The basic method of investigation was the molecular dynamics simulation of 3D protein models in an explicit solvent at different temperatures (300 and 373 K). Some thermolabile regions in Trx, BacTrx, and their mutants were revealed by analyzing the temperature effect on the molecular dynamics of the protein molecule. The effect of single point mutations on the temperature changes of the protein conformation flexibility in several thermolabile regions was found. The results of the simulations are in accord with experimental data indicating that the mutation E85R increases Trx thermostability, whereas the mutation R82E decreases BacTrx thermostability. The thermostability of these proteins was revealed to depend on ionic interactions between the thermolabile regions. The single point mutations change the parameters of these interactions and make them more favorable in the E85R-Trx mutant and less favorable in the R82E-BacTrx mutant.
Russian Journal of Bioorganic Chemistry 08/2004; 30(5):421-430. · 0.64 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The hypothesis that local conformational differences of the snake venom cardiotoxins (cytotoxins, CT) may play a significant role in their interaction with membrane was tested by molecular modeling of the behavior of the CT A5 from the venom of Naja atra in water and at the water–membrane interface. Two models of the CT A5 spatial structure are known: the first was obtained by X-ray analysis and the second, by NMR studies in solution. A molecular dynamics (MD) analysis demonstrated that loop II of the toxin has a fixed -like shape in water, which does not depend on its initial structure. An interaction of the experimentally derived (X-ray and NMR) conformations and MD simulated conformations of CT A5 with the lipid bilayer was studied by the Monte Carlo method using the previously developed model of the implicit membrane. It is found that: (1) unlike the previously studied CT2 from the venom of cobra Naja oxiana, CT A5 has only loops I and II bound to the membrane with the involvement of a lesser number of hydrophobic residues. (2) A long hydrophobic area is formed on the surface of CT A5 due to the -like shape of loop II and the arrangement of loop I in proximity to loop II. This hydrophobic area favors the toxin embedding into the lipid bilayer. (3) The toxin retains its conformation upon interaction with the membrane. (4) The CT A5 molecule has close values of the potential energy in the membrane and in aqueous environment, which suggests dynamic character of the binding. The results of the molecular modeling indicate a definite configuration of loops I and II and, consequently, a specific character of distribution of polar and apolar properties on the toxin surface, which turns out to be the most energetically favorable.
Russian Journal of Bioorganic Chemistry 10/2003; 29(6):523-533. · 0.64 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Zervamicin IIB is a 16-amino acid peptaibol that forms voltage-dependent ion channels with multilevel conductance states in planar lipid bilayers and vesicular systems. The spatial structure of zervamicin IIB bound to dodecylphosphocholine micelles was studied by nuclear magnetic resonance spectroscopy. The set of 20 structures obtained has a bent helical conformation with a mean backbone root mean square deviation value of approximately 0.2 A and resembles the structure in isotropic solvents (Balashova et al., 2000. NMR structure of the channel-former zervamicin IIB in isotropic solvents. FEBS Lett 466:333-336). The N-terminus represents an alpha-helix, whereas the C-terminal part has a mixed 3(10)/alpha(R) hydrogen-bond pattern. In the anisotropic micelle environment, the bending angle on Hyp10 (23 degrees) is smaller than that (47 degrees) in isotropic solvents. In the NOESY (Nuclear Overhauser Effect Spectroscopy) spectra, the characteristic attenuation of the peptide signals by 5- and 16-doxylstearate relaxation probes indicates a peripheral mode of the peptaibol binding to the micelle with the N-terminus immersed slightly deeper into micelle interior. Analysis of the surface hydrophobicity reveals that the zervamicin IIB helix is amphiphilic and well suited to formation of a tetrameric transmembrane bundle, according to the barrel-stave mechanism. The results are discussed in a context of voltage-driven peptaibol insertion into membrane.
Biophysical Journal 03/2002; 82(2):762-71. · 3.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The conformational space of a hydrophobic peptide fragment of glycophorin A in a lipid membrane was studied with the Monte Carlo method using the solvation model described in the first communication of this series. The simulation was performed for various starting orientations of the peptide relative to the membrane bilayer: outside, inside, partially immersed, and transbilayer. We showed that the membrane substantially stabilizes the alpha-helical conformation of the central hydrophobic part of the glycophorin A molecule, which for the most part is immersed in the apolar core of the bilayer. For various conformational states, energy values were calculated and the orientations of the peptide relative to the membrane were characterized. Depending on the thickness of the bilayer, either an entirely alpha-helical conformation in transbilayer orientation or a conformation with a kink in the central part of the helix with the N- and C-termini exposed on one side of the membrane corresponds to the minimal-energy structure. The transmembrane orientation of glycophorin A is energetically advantageous when the membrane thickness is close to the length of its hydrophobic helical portion, which is consistent with the effect of "hydrophobic match" observed experimentally. The prospects for further refinement of the model are discussed.
Bioorganicheskaia khimiia 04/2000; 26(3):163-72.
-
[show abstract]
[hide abstract]
ABSTRACT: A theoretical solvation model of peptides and proteins that mimics the heterogeneous membrane-water system was proposed. Our approach is based on the combined use of atomic parameters of solvation for water and hydrocarbons, which approximates the hydrated polar groups and acyl chains of lipids, respectively. This model was tested in simulations of several peptides: a nonpolar 20-mer polyleucine, a hydrophobic peptide with terminal polar groups, and a strongly amphiphilic peptide. The conformational space of the peptides in the presence of the membrane was studied by the Monte Carlo method. Unlike a polar solvent and vacuum, the membrane-like environment was shown to stabilize the alpha-helical conformation: low-energy structures have a helicity index of 100% in all cases. At the same time, the energetically most favorable orientations of the peptides relative to the membrane depend on their hydrophobic properties: nonpolar polyleucine is entirely immersed in the bilayer and the hydrophobic peptide with polar groups at the termini adopts a transbilayer orientation, whereas the amphiphilic peptide lies at the interface parallel to the membrane plane. The results of the simulations agree well with the available experimental data for these systems. In the following communications of this series, we plan to describe applications of the solvation model to membrane-bound proteins and peptides with biologically important functional activities.
Bioorganicheskaia khimiia 03/2000; 26(2):130-40.
