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Ефремов Роман Гербертович

Московский институт электроники и математики им. А.Н. Тихонова

Профиль на hse.ru ↗ тел.: +7 (495) 916-88-76 | 15129 | +7 (903) 743-16-56
Публикаций
127
Языков
2
Наград
5
Конференций
3
Профиль Публикации (127) Курсы (4)

Профессиональные интересы

Вычислительная биологиякомпьютерная биологиямолекулярное моделированиеструктура и динамика биомолекулбиофизика

Должности

  • Профессор — Московский институт электроники и математики им. А.Н. Тихонова, Департамент прикладной математики

Био

  • · Начал работать в НИУ ВШЭ в 2013 году.
  • · Научно-педагогический стаж: 42 года.

Образование

  • 2007 · Ученое звание: Профессор
  • 2000 · Доктор физико-математических наук
  • 1986 · Кандидат физико-математических наук
  • 1983 · Специалитет: Московский инженерно-физический институт, специальность «Дозиметрия и защита», квалификация «Инженер-физик»

Награды и поощрения

  • · Участие в научных советах и обществах: член Ученого Совета ИБХ РАН; член трех специализированных диссертационных советов (ИБХ РАН, МГУ, ГУ НИИ БМХ РАМН); член Американского химического общества; член Биофизического общества (США).
  • · Надбавка за публикацию в журнале из Списка А (и приравненном к нему научном издании) (2025–2026, 2024–2025, 2023–2024)
  • · Надбавка за публикацию в международном рецензируемом научном издании (2022–2023, 2021–2022, 2019–2021)
  • · Надбавка за статью в зарубежном рецензируемом журнале (2014–2016)
  • · Надбавка за статью в зарубежном рецензируемом научном издании (2016–2018)

Гранты и проекты

  • 2016 · Грант Российского научного фонда «Компьютерный анализ структурно-функциональных аспектов олигомеризации трансмембранных доменов рецепторов сигнальных систем клетки», 2014-2016 гг., руководитель.
  • 2016 · Грант Российского научного фонда «Молекулярные технологии управления нейросигнализацией», 2014-2016 гг., отв. соисполнитель.
  • 2017 · Грант Программы Президиума РАН «Молекулярная и клеточная биология», тема: «Молекулярное моделирование пептидов и белков в мембранах как фундаментальная основа для рационального конструирования новых биологически активных соединений», 2013-2017 гг., руководитель.
  • 2014 · Грант Программы Президиума РАН № 27 «Основы фундаментальных исследований нанотехнологий и наноматериалов», тема: «Новые вычислительные технологии мультимасштабного моделирования мезоскопических биомембранных систем: от понимания фундаментальных принципов структурно-динамического поведения – к созданию наноструктур для биомедицинских приложений», 2012-2014 гг., руководитель.
  • 2015 · Грант РФФИ «Коллективные молекулярные движения, кластеры и флуктуации в гидратированных липидных бислоях и их роль в структурно-динамическом поведении клеточных мембран», 2013-2015 гг., руководитель.
  • 2018 · Грант РФФИ «Клеточные мембраны как стохастические динамические системы: от атомистического моделирования – к рациональному конструированию новых мембранных материалов», 2016-2018 гг., руководитель.

Конференции (3)

Показать все
  • · 2016: Актуальные вопросы биологической физики и химии БФФХ-2016 (Севастополь). Доклад: Оценка влияния среды на димеризацию трансмембранных доменов гликофорина А в компьютерном эксперименте
  • · 2016: Khujand Symposium on Computational Materials and Biological Sciences 2016 (Худжанд). Доклад: Helix-helix interactions in membranes: focus on lipids
  • · 2014: Dushanbe Symposium on Computational Materials and Biological Sciences DSCMBS-2014 (Душанбе). Доклад: The adaptable lipid matrix promotes transmembrane helices association in membranes

Идентификаторы исследователя

Публикации (127)

Dielectric-dependent strength of interlipid H-bonding in biomembranes: a model case study.

2019 · ARTICLE · en

Atomistic aspects of the structural organization, dynamics, and functioning of hydrated lipid bilayers - model cell membranes - are primarily governed by the fine balance of intermolecular interactions between all constituents of these systems. Besides the hydrophobic effect, which shapes the overall skeleton of lipid membranes, very important contribution to their behavior is made by hydrogen bonds (H-bonds) between lipid head groups. The latter determine such crucial phenomena in cell membranes, like dynamic ultra-nanodomain organization, hydration, fine-tuning of microscopic physico-chemical properties that allow the membrane to adapt quickly when binding/insertion external agents (proteins, etc.) The characteristics of such H-bonds (strength, spatial localization, etc.) dramatically depend on the local polarity properties of the lipid-water environment. In this work, we calculated free energies of H-bonded complexes between typical donor (NH3+, NH, OH) and acceptor (C=O, OH, COO-, COOH) groups of lipids in vacuo and in a set of explicit solvents with dielectric constants (ε) from 1 to 78.3, which mimic membrane environment at different depth. This was done using Monte Carlo simulations and an assessment of the corresponding Potential of Mean Force profiles. The strongest H-bonded complexes were observed in the nonpolar environment and their strength increased sharply with decreasing ε below 17. When ε changed, the largest free energy gain (> 10.8 kcal/mol) was observed for pairs of acceptors C=O and O(H) with donor NH3+. The complexation of the same acceptors with NH-donor in this range of ε was rather less sensitive to the environmental polarity: by ~1.5 kcal/mol. Dielectric-dependent interactions of polar lipid groups with water were evaluated as well. The results explain the delicate balance that determines the unique pattern of H-bonds for a particular lipid bilayer. Understanding the factors that regulate the propensity to H-bonding in lipid bilayers provides a fundamental basis for the rational design of new membrane nano-objects with predefined properties.

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Familial L723P Mutation Can Shift the Distribution between the Alternative APP Transmembrane Domain Cleavage Cascades by Local Unfolding of the Ε‑Cleavage Site Suggesting a Straightforward Mechanism of Alzheimer’s Disease Pathogenesis.

2019 · ARTICLE · en

Alzheimer’s disease is an age-related pathology associated with accumulation of amyloid-β peptides, products of enzymatic cleavage of amyloid-β precursor protein (APP) by secretases. Several familial mutations causing early onset of the disease have been identified in the APP transmembrane (TM) domain. The mutations influence production of amyloid-β, but the molecular mechanisms of this effect are unclear. The “Australian” (L723P) mutation located in the C-termini of APP TM domain is associated with autosomal-dominant, early-onset Alzheimer’s disease. Herein, we describe the impact of familial L723P mutation on the structural-dynamic behavior of APP TM domain studied by high-resolution NMR in membrane-mimicking micelles and augmented by molecular dynamics simulations in explicit lipid bilayer. We found L723P mutation to cause local unfolding of the C-terminal turn of the APP TM domain helix and increase its accessibility to water required for cleavage of the protein backbone by γ-secretase in the ε-site, thus switching between alternative (“pathogenic” and “non-pathogenic”) cleavage cascades. These findings suggest a straightforward mechanism of the pathogenesis associated with this mutation, and are of generic import for understanding the molecular-level events associated with APP sequential proteolysis resulting in accumulation of the pathogenic forms of amyloid-β. Moreover, age-related onset of Alzheimer’s disease can be explained by a similar mechanism, where the effect of mutation is emulated by the impact of local environmental factors, such as oxidative stress and/or membrane lipid composition. Knowledge of the mechanisms regulating generation of amyloidogenic peptides of different lengths is essential for development of novel treatment strategies of the Alzheimer’s disease.

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Protein Surface Topography as a tool to enhance the selective activity of a potassium channel blocker

2019 · ARTICLE · en

Tk-hefu is an artificial peptide designed based on the α-hairpinin scaffold, which selectively blocks voltage-gated potassium channels Kv1.3. Here we present its spatial structure resolved by NMR spectroscopy and analyze its interaction with channels using computer modeling. We apply protein surface topography to suggest mutations and increase Tk-hefu affinity to the Kv1.3 channel isoform. We redesign the functional surface of Tk-hefu to better match the respective surface of the channel pore vestibule. The resulting peptide Tk-hefu-2 retains Kv1.3 selectivity and displays ∼15 times greater activity compared with Tk-hefu. We verify the mode of Tk-hefu-2 binding to the channel outer vestibule experimentally by site-directed mutagenesis. We argue that scaffold engineering aided by protein surface topography represents a reliable tool for design and optimization of specific ion channel ligands.

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Confined dynamics of water in transmembrane pore of TRPV1 ion channel

2019 · ARTICLE · en

Solvation effects play a key role in chemical and biological processes. The microscopic properties of water near molecular surfaces are radically different from those in the bulk. Furthermore, behavior of water in confined volumes of nanometer scale, including transmembrane pores of ion channels, is especially nontrivial. Knowledge at the molecular level of structural and dynamic parameters of water in such systems is necessary to understand the mechanisms of ion channels functioning. In this work, the results of molecular dynamics (MD) simulations of water in the pore and selectivity filter domains of TRPV1 membrane channel are considered. These domains represent nanoscale volumes with strongly amphiphilic walls, where physical behavior of water radically differs from that of free hydration (e.g., at protein interfaces) or in the bulk. Inside the pore and filter domains, water reveals very heterogeneous spatial distribution and unusual dynamics: it forms compact areas localized near polar groups of particular residues. Residence time of water molecules in such areas is at least 1.5-3 times larger than that observed for similar groups at the protein surface. Presumably, these water “blobs” play an important role in functional activity of TRPV1. In particular, they take a part in hydration of the hydrophobic TRPV1 pore by localizing up to 6 waters near the so-called “lower gate” of the channel and reducing by this way the free energy barrier for ion and water transport. Although the channel is formed by four identical protein subunits, which are symmetrically packed in the initial experimental 3D structure, in the course of MD simulations, hydration of the same amino acid residues of individual subunits may differ significantly. This greatly affects the microscopic picture of the distribution of water in the channel and, potentially, the mechanism of its functioning. Therefore, reconstruction the full picture of the TRPV1 channel solvation requires a thorough atomistic simulations and analysis. It is important that the naturally occurred porous volumes like ion conducting protein domains reveal much more sophisticated and fine-tuned regulation of solvation than, e.g. artificially designed carbon nanotubes.

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Structural basis of the signal transduction via transmembrane domains of type I receptors in norma and pathology

2019 · CHAPTER · en

The human epidermal growth factor (EGFR/HER) and growth hormone (GHR) receptors serve as excellent models of type I receptors to illustrate how ligand-induced conformational rearrangements and specific dimerization of extracellular domains lead to the allosteric activation of the cytoplasmic domains via single-span transmembrane domain (TMD). We determined the alternative dimeric conformations of the EGFR and GHR TMDs in different membrane-mimicking environments using high-resolution NMR spectroscopy combined with MD-relaxation in explicit lipid bilayer. Based on the location of pathogenic transmembrane mutations, observed conformations correspond to the dormant and active states of both receptors, assuming an impact of intramembrane interactions to the cell signaling dysfunction in human organism. Fine adaptation of intermolecular polar and hydrophobic contacts that we found to accompany the different EGFR TMD dimerizations suggests that certain membrane properties can govern the TMD helix-helix packing and, thus, their alteration can trigger the receptor state. Whereas two distinct dimeric modes of GHR TMD revealed the functional role of juxtamembrane region rearrangements in alternation between protein-protein and protein-lipid interactions that can be initiated by ligand binding. Observed the TMD helix-helix packing diversity appears in favor of the lipid-mediated rotationcoupled activation mechanism, which implies that the sequence of structural rearrangements of EGFR and GHR domains is associated with perturbations of the lipid bilayer in the course of ligand-induced receptor activation, considering the receptor together with its lipid environment as a self-consistent signal transduction system.

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Mode of action and biological activity of sevanol and its analogues on acid-sensing ion channels

2019 · CHAPTER · en

Acid-sensing ion channels (ASICs), members of the family of amiloride-sensitive degenerin/epithelial Na + -channels, are expressed in neurons of both the peripheral and central nervous system. Among six currently known isoforms of mammalian ASICs, two, namely ASIC1a and ASIC3 are widespread and have the largest physiological contribution such as synaptic plas- ticity, learning and memory as well as pain perception and inflammation development. We have previously shown that seva- nol, a new lignan isolated from Thymus armeniacus, inhibits ASIC1a and ASIC3 currents and exerts analgesic and anti- inflammatory effects when administered intravenously. Here we present a scheme for the synthesis of sevanol, which was devel- oped for the first time. In addition, sevanol analogues were syn- thesized, in which the basic core of the molecule of epiphyllic acid remained unchanged, while substituents for carboxyl groups in positions 9,10 were modified. These analogues demonstrate a clear correlation between the activity of the molecule and the number of free carboxyl groups in it. Using molecular modeling and analysis of the activity of sevanol in the presence of ASIC1a potentiator, an RF-amide peptide, we established a possible bind- ing site for sevanol on the channel. We also showed that with intranasal administration, sevanol can have the same effective analgesic effect as with intravenous administration. Such struc- tural and functional analysis demonstrates a correlation between the inhibitory effect value and the number of functional groups of the molecule, which may be important for the rational design of biologically active sevanol-based compounds.

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Dimerization of transmembrane domain of insulin receptor: structure and possible role in activation

2019 · CHAPTER · en

Insulin receptor (IR) family is represented by three membrane proteins participating in organism development, growth, and vital activity. Modulation of the functioning of these receptors by external agents looks very perspective from a pharmaceutical point of view. Although IR is well studied, little is known about the role of its transmembrane (TM) domain in receptor activity. Nowadays, the major model of signal transfer by these receptors describes ligand-triggered conformational changes in the extracellular domain, bringing together TM domains that dimerize. This allows trans-autophosphorylation of intracellular domains followed by activation of secondary messengers. However, the conformation of the TM dimeric state is still unknown. Here, we studied in silico dimerization of TM segments of two closest members of the family: IR and IGF-1R. As a result, TM dimeric structures were predicted. This was done taking into account available structural data on extra- and intracellular parts of the receptors. Inspection of the extracellular segment mobility in the basal state revealed several modes of protein motion, although none of them allow TM domain dimerization. The calculated molecular dynamics of TM helices linked to intracellular domain led to a conclusion about autonomic behavior of the TM domain. Based on this data, the dimerization of TM domains was further simulated without extramembrane parts. The most probable models of TM dimeric structures were predicted and the free energy of helix-helix association in explicit lipid bilayers was evaluated. Two most energetically favorable models for IR and one for IGF-1R were delineated. Despite the lack of sequence homology, TM segments in both receptors pack in similar parallel dimers, thus suggesting a close activation mechanism.

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Protein–lipid interactions in glycophorin-like dimerization motifs of transmembrane helices

2019 · CHAPTER · en

Receptor tyrosine kinases (RTK) are vital players in cell signaling governing growth and proliferation. These integral membrane proteins work only in dimeric states, so the conformation of transmembrane dimer determines the signal transferred into cell. Here, we used modern molecular modeling techniques to study details of protein-protein and protein-lipid interactions in model systems containing monomers and dimers of several receptor tyrosine kinases with glycophorin-like dimerization motifs. Comparison of structural and dynamic aspects of ErbB family members and glycophorin A (GpA) revealed similarities in their properties, especially, for ErbB1, ErbB2 and ErbB4 receptors utilizing the same GpA-like motif for dimerization in their basal state. We demonstrated that they all have similar organization of TM domain’s molecular surface in terms of both relief, hydrophobic properties and lipid binding sites resembling GpA pattern studied before. All these RTKs strongly interact with lipid acyl chains, forming stable binding sites both in monomeric and dimeric states, and the most prominent binding areas are located in monomers on the future GpA-like dimerization interfaces. Then, lipids distribution changes upon dimer formation. This is not the case for alternative packing geometries observed for the second state of ErbB1 and, especially, ErbB3. We found higher numbers of immobilized lipids near C-terminus in ErbB1 and ErbB2 active dimers, thus assuming that the existing structure of ErbB3 is also active. However, there is non-functional GpA-like motif in ErbB3 with some bound lipids present near the N-terminus, suspecting another structure for inactive receptor. However, despite considerable similarities, these RTKs have different hydrophobicity distributions along helices, that can be important in terms of preferable lipid environment. The work was funded by the Russian Academic Excellence Project ‘5-100’ and Russian Foundation for Basic Research grant 18-54-15007.

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Nisin/lipid II interaction in bacterial membrane: molecular dynamics study

2019 · CHAPTER · en

The worldwide rapid emergence of resistant bacteria put at threat the efficacy of antibiotics, thus the development of novel antibacterial agents is urgently needed. The cell wall precursor lipid II consisting the chemically conservative pyrophosphate group represents a promising pharmaceutical target. Antimicrobial peptides, that target lipid II, i.e. lantibiotic nisin, could be excellent prototypes for new generation antibiotics due to their low liability to develop resistance. Understanding of molecular mechanism of initial stages of membrane-bound lipid II recognition by water-soluble nisin is indispensable, in order to improve the peptide structure and properties into pharmaceutically applicable form. Here, we present a molecular dynamics simulation study of initial stages of the aforementioned recognition. In membrane environment, lipid II adopts very few conformations characterized by unique spatial arrangement of hydrogen bond acceptors in the pyrophosphate group at the bilayer surface. These acceptors are efficiently captured by NH groups of nisin, thus explaining its high selectivity to lipid II. Similarly, rings A and B of nisin, which are known to recognize lipid II, adopt the only stable conformation in the presence of dimethylpyrophosphate, which mimics the binding determinant of lipid II. Finally, we propose molecular model of nisin (rings A and B) / lipid II complex in bacterial membrane, which may be employed for design of novel antibiotic prototypes.

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Effects of interfering transmembrane peptides on neuraminidase-1 activity

2019 · CHAPTER · en

Elastin is an essential component of numerous human tissues and plays a critical role in elasticity of skin, lungs and arteries. During vascular aging, the elastin network is degraded generating elastin-derived peptides (EDP). The ERC (Elastin Receptor Complex) is a membrane heterotrimeric receptor composed, amongst others, of a membrane-bound neuraminidase, NEU-1. Binding of EDP to the ERC induces the activation of signaling pathways associated with biological effects notably the development of diseases such as atherosclerosis, cancer and diabetes. Previous studies of our laboratory have shown that NEU-1 catalytic activity is linked to its ability to homodimerize. Thus, NEU-1 constitutes a key pharmacological target to fight against deleterious effects of EDP. The aim of this work is to develop by biological/biochemical experiments and molecular dynamic (MD) simulations a transmembrane interfering peptide (pI) able to inhibit specifically NEU-1 dimerization. Peptides are delivered into cells using two strategies, TAT peptides, which are cell-penetrating peptides, or lithium dodecyl sulfate micelles. No cellular toxicity was observed in both approaches. Confocal microscopy underlines a colocalization between pI and NEU-1 at the plasma membrane and coimmunoprecipitation experiments show an interaction between pI and NEU-1. Furthermore, sialidase activity assays point out the ability of pI to inhibit NEU-1 homodimerization (47%; 51%) and its associated sialidase activity (21%; 47%). Preliminary MD simulation studies emphasize that both pI and the transmembrane domain of NEU-1 are stable and helix integrity is conserved in lipid bilayer environments. Moreover, the formation of a spontaneous dimer between NEU-1 and pI was identified. Further MD analyses underline the bio- logical relevance of our membrane model. These results reveal the ability of pI to bind to NEU-1, inhibit its dimerization and sialidase activity.

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Курсы (4)