DSA Faculty
API
← к списку преподавателей

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)

Temperature-sensitive gating of TRPV1 channel as probed by atomistic simulations of its trans- and juxtamembrane domains

2016 · ARTICLE · en

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.

DOI ↗ PDF ↗

High-Affinity α-Conotoxin PnIA Analogs Designed on the Basis of the Protein Surface Topography Method.

2016 · ARTICLE · en

Despite some success for small molecules, elucidating structure–function relationships for biologically active peptides — the ligands for various targets in the organism — remains a great challenge and calls for the development of novel approaches. Some of us recently proposed the Protein Surface Topography (PST) approach, which benefits from a simplified representation of biomolecules’ surface as projection maps, which enables the exposure of the structure–function dependencies. Here, we use PST to uncover the “activity pattern” in α-conotoxins — neuroactive peptides that effectively target nicotinic acetylcholine receptors (nAChRs). PST was applied in order to design several variants of the α-conotoxin PnIA, which were synthesized and thoroughly studied. Among the best was PnIA[R9, L10], which exhibits nanomolar affinity for the α7 nAChR, selectivity and a slow wash-out from this target. Importantly, these mutations could hardly be delineated by “standard” structure-based drug design. The proposed combination of PST with a set of experiments proved very efficient for the rational construction of new bioactive molecules.

DOI ↗ PDF ↗

Secreted Isoform of Human Lynx1 (SLURP-2): Spatial Structure and Pharmacology of Interactions with Different Types of Acetylcholine Receptors.

2016 · ARTICLE · en

Human-secreted Ly-6/uPAR-related protein-2 (SLURP-2) regulates the growth and differentiation of epithelial cells. Previously, the auto/paracrine activity of SLURP-2 was considered to be mediated via its interaction with the α3β2 subtype of the nicotinic acetylcholine receptors (nAChRs). Here, we describe the structure and pharmacology of a recombinant analogue of SLURP-2. Nuclear magnetic resonance spectroscopy revealed a ‘three-finger’ fold of SLURP-2 with a conserved β-structural core and three protruding loops. Affinity purification using cortical extracts revealed that SLURP-2 could interact with the α3, α4, α5, α7, β2, and β4 nAChR subunits, revealing its broader pharmacological profile. SLURP-2 inhibits acetylcholine-evoked currents at α4β2 and α3β2-nAChRs (IC50 ~0.17 and >3 μM, respectively) expressed in Xenopus oocytes. In contrast, at α7-nAChRs, SLURP-2 significantly enhances acetylcholine-evoked currents at concentrations

DOI ↗ PDF ↗

Central loop of non-conventional toxin WTX from Naja kaouthia is important for interaction with nicotinic acetylcholine receptors.

2016 · ARTICLE · en

‘Three-finger’ toxin WTX from Naja kaouthia interacts with nicotinic and muscarinic acetylcholine receptors (nAChRs and mAChRs). Mutagenesis and competition experiments with 125I-α-bungarotoxin revealed that Arg31 and Arg32 residues from the WTX loop II are important for binding to Torpedo californica and human α7 nAChRs. Computer modeling suggested that loop II occupies the orthosteric binding site at α7 nAChR. The similar toxin interface was previously described as a major determinant of allosteric interactions with mAChRs.

DOI ↗ PDF ↗

New Insights into Molecular Organization of Human Neuraminidase-1: Transmembrane Topology and Dimerization Ability

2016 · ARTICLE · en

Neuraminidase 1 (NEU1) is a lysosomal sialidase catalyzing the removal of terminal sialic acids from sialyloconjugates. A plasma membrane-bound NEU1 modulating a plethora of receptors by desialylation, has been consistently documented from the last ten years. Despite a growing interest of the scientific community to NEU1, its membrane organization is not understood and current structural and biochemical data cannot account for such membrane localization. By combining molecular biology and biochemical analyses with structural biophysics and computational approaches, we identified here two regions in human NEU1 - segments 139–159 (TM1) and 316–333 (TM2) - as potential transmembrane (TM) domains. In membrane mimicking environments, the corresponding peptides form stable α-helices and TM2 is suited for self-association. This was confirmed with full-size NEU1 by co-immunoprecipitations from membrane preparations and split-ubiquitin yeast two hybrids. The TM2 region was shown to be critical for dimerization since introduction of point mutations within TM2 leads to disruption of NEU1 dimerization and decrease of sialidase activity in membrane. In conclusion, these results bring new insights in the molecular organization of membrane-bound NEU1 and demonstrate, for the first time, the presence of two potential TM domains that may anchor NEU1 in the membrane, control its dimerization and sialidase activity.

DOI ↗ PDF ↗

Оценка влияния среды на димеризацию трансмембранных доменов гликофорина А в компьютерном эксперименте

2016 · CHAPTER · ru

азработан комплексный подход к изучению взаимного влияния белка и мембранной среды в процессе димеризации трансмембранных (ТМ) α-спиральных пептидов. В основе подхода – численное разложение профилей свободной энергии взаимодействия ТМ- спиралей на компоненты, соответствующие различным типам взаимодействий, и картирование пространственного распределения средней плотности липидов. Метод апробирован для ТМ-сегментов гликофорина А человека (GpA) и нескольких модельных пептидов. Показано, что липиды вносят значительный выгодный вклад в свободную энергию димеризации, в то время как образующиеся на интерфейсе мономеров контакты аминокислотных остатков могут, наоборот, быть невыгодными. Также на боковой поверхности ТМ-доменов GpA показано наличие сайтов связывания ацильных цепей молекул липидов. Таким образом, аминокислотная последовательность белка определяет и белок- белковые взаимодействия, и связывание липидов, что влияет на детальное распределение энергетических вкладов. При этом липидная мембрана может выступать в качестве непосредственного участника спонтанной ассоциации ТМ α-спиралей. Результаты данной работы могут быть использованы для рационального конструирования перспективных пептидных модуляторов, направленных на корректировку работы битопных мембранных белков, включая рецепторные тирозинкиназы.

PDF ↗

Temperature-sensitive gating of TRPV1 channel as probed by atomistic simulations of its trans- and juxtamembrane domains

2016 · ARTICLE · en

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.

DOI ↗ PDF ↗

Cobra cytotoxins: determinants of antibacterial activity

2015 · ARTICLE · en

The investigation of antibacterial activity of three-finger cobra cytotoxins towards Gram-negative and Gram-positive bacteria showed no activity against the former species, whereas M. luteus was found most susceptible to cytotoxins. A correlation was revealed between this activity and hydrophobicity of the toxins (HTL scores), total charge and its distribution over the toxin molecule: the absence of Glu-16 residue and the presence of positively charged residues (Lys30/His31) in the tip of the loop 2

DOI ↗ PDF ↗

Рациональное конструирование новых лигандов никотиновых рецепторов на основе альфа-конотоксина PnIA

2015 · ARTICLE · ru

Настоящее исследование продолжает предыдущую работу и нацелено на создание более эффективного лиганда α 7 нАХР на основе α -конотоксина PnIA. На этот раз мы использовали разработанный в Институте биоорганической химии им. М.М. Шемякина и Ю.А. Овчинникова РАН вычислительный метод “белковой топографии” (PST, protein surface topography) и впервые применили его для выбора нужных мутаций в конотоксинах.

PDF ↗

Latarcins: versatile spider venom peptides

2015 · ARTICLE · en

Arthropod venoms feature the presence of cytolytic peptides believed to act synergetically with neurotoxins to paralyze prey or deter aggressors. Many of them are linear, i.e., lack disulfide bonds. When isolated from the venom, or obtained by other means, these peptides exhibit common properties. They are cationic; being mostly disordered in aqueous solution, assume amphiphilic α-helical structure in contact with lipid membranes; and exhibit general cytotoxicity, including antifungal, antimicrobial, hemolytic, and anticancer activities. To suit the pharmacological needs, the activity spectrum of these peptides should be modified by rational engineering. As an example, we provide a detailed review on latarcins (Ltc), linear cytolytic peptides from Lachesana tarabaevi spider venom. Diverse experimental and computational techniques were used to investigate the spatial structure of Ltc in membrane-mimicking environments and their effects on model lipid bilayers. The antibacterial activity of Ltc was studied against a panel of Gram-negative and Gram-positive bacteria. In addition, the action of Ltc on erythrocytes and cancer cells was investigated in detail with confocal laser scanning microscopy. In the present review, we give a critical account of the progress in the research of Ltc. We explore the relationship between Ltc structure and their biological activity and derive molecular characteristics, which can be used for optimization of other linear peptides. Current applications of Ltc and prospective use of similar membrane-active peptides are outlined. © 2015 Springer Basel

DOI ↗ PDF ↗

Курсы (4)