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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)

Structural mechanism of heat-induced opening of a temperature-sensitive TRP channel

2021 · ARTICLE · en

Numerous physiological functions rely on distinguishing temperature through temperature-sensitive transient receptor potential channels (thermo-TRPs). Although the function of thermo-TRPs has been studied extensively, structural determination of their heat- and cold-activated states has remained a challenge. Here, we present cryo-EM structures of the nanodisc-reconstituted wild-type mouse TRPV3 in three distinct conformations: closed, heat-activated sensitized and open states. The heat-induced transformations of TRPV3 are accompanied by changes in the secondary structure of the S2-S3 linker and the N and C termini and represent a conformational wave that links these parts of the protein to a lipid occupying the vanilloid binding site. State-dependent differences in the behavior of bound lipids suggest their active role in thermo-TRP temperature-dependent gating. Our structural data, supported by physiological recordings and molecular dynamics simulations, provide an insight for understanding the molecular mechanism of temperature sensing.

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Insulin and IGF-1 receptors transmembrane domain dimers: structure prediction and possible role in activation

2021 · ARTICLE · en

The receptor tyrosine kinase (RTK) superfamily comprises many different cell-surface receptors having similar membrane organization and function with signal transduction occuring in the dimeric state. Insulin receptor (IR) and type 1 insulin-like growth factor receptor (IGF1R) differ from other RTKs being constitutively homodimeric transmembrane glycoproteins, and molecular mechanisms of their activation still remain elusive. Current hypothesis suggests ligand-triggered structural changes in the extracellular domain followed by transmembrane (TM) domains closure and dimerization leading to kinase activity in intracellular segments of the receptor. Using experimental data as constraints, we proposed several atomistic models of dimeric states of IR and IGF-1R TM domains. Molecular dynamics simulations of IR ectodomain revealed noticeable collective movements potentially responsible for closure of its C-termini corresponding to spatial approaching of the following TM helices. Also, we demonstrated that the juxtamembrane part of the IR does not impose strong restrictions on the positioning of TM helices. Finally, we utilized two independent structure prediction methods to generate a series of TM dimer conformations followed by cluster analysis and dimerization free energy estimation to select the best dimer models. Biological relevance of the later was further tested via comparison of the hydrophobic organization of TM helices for both wild-type receptors and two their mutants. Based on these data, the role of several TM segments from other proteins in activation of IR and/or IGF-1R was explained. The elaborated models can be used for rational design of new factors modulating insulin signaling.

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Structural and dynamic properties of type A (I) lantibiotics determining their binding to lipid II

2021 · ARTICLE · en

Antibiotic resistance is one of the biggest public health challenges of our time and this is the motivation for finding new antibiotics. A class of bacteriocins — lantibiotics – are promising agents for drug discovery. Lantibiotics are ribosomally synthesized and posttranslationally modified cationic antimicrobial peptides. The specific target of type A (I) lantibiotics is the pyrophosphate moiety (PPi) of lipid II. Nisin, gallidermin, and epidermin are the main peptides in this class of bacteriocins. In binding to the lipid II the main role is played by residues 1–12. The aim of the study was to explore the structural properties of these lantibiotics’ fragments in the presence of dimethyl pyrophosphate ion (DMPPi) that mimics PPi of lipid II via molecular dynamics (MD) simulations in water. It was shown that nisin 1–12 forms 4–5 intermolecular hydrogen bonds (H-bonds) with DMPPi, while gallidermin 1–12 and epidermin 1–12 create 6–7 H-bonds, mainly via backbone NH groups of the ring A. This fact correlates with experimental data on higher antimicrobial activity of gallidermin and epidermin. For the studied antibiotics, we found a similar conformation, in which the largest number of intermolecular H-bonds was formed. In this conformation, the rings A and B are placed opposite each other, thus being stabilized by two intramolecular H-bonds in the case of nisin (Dha5-Dab8 and Dha5-Pro9) and one H-bond in the case of gallidermin/epidermin (Lys4-Dab8). In nisin, gallidermin, and epidermin, the MD-derived lifetime of the aforementioned state are 28%, 85%, and 88%, respectively. The significant difference between nisin and gallidermin/epidermin is the position of the NH group of 5th residue, which is turned towards DMPPi in the latter case. It has been shown that lantibiotics of type A (I) are able to form stable complexes of a similar structure with the PPi mimetic of lipid II, and the residue 5 affects the binding.

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In silico study of nisin/lipid II molecular recognition

2021 · ARTICLE · en

Given the challenge of global antibiotic resistance, the development of new medications is indispensable. Lipid II - bacterial cell wall precursor – is a promising pharmaceutical target for innovative antibiotics, whereas lantibiotic nisin, effectively capturing lipid II’s conservative pyrophosphate group, is a potential prototype of a new generation of antibiotics. Because the structure of membrane-bound lipid II/nisin complex is lacking, we studied their recognition via molecular dynamics (MD) simulations. As a result, the medium-driven dynamics of both partners in their parent environments was explored. The N-terminal 11-residue fragment of nisin, which recognizes lipid II in bacterial membrane, adopts a unique closed-ring conformation only in water solution - this was proven by recent NMR study. In this state, the peptide NH groups of the ring A orient toward a common center, forming a pool of H-bond donors. Based on MD data, it was shown that nisin in this conformation forms the most stable complex with pyrophosphate analogues mimicking the binding determinant of lipid II. Here, we describe the results of the detailed in silico study of nisin1-11 structure and dynamics in different solvents. Efficient conformational sampling and clustering of the MD states based on backbone coordinates and dihedral angles was performed. The results obtained were found to be environment-dependent. These findings may be further employed to improve the peptide structure in order to design its new pharmaceutically applicable forms.

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Human Three-Finger Protein Lypd6 Is a Negative Modulator of the Cholinergic System in the Brain

2021 · ARTICLE · en

Lypd6 is a GPI-tethered protein from the Ly-6/uPAR family expressed in the brain. Lypd6 enhances the Wnt/β-catenin signaling, although its action on nicotinic acetylcholine receptors (nAChRs) have been also proposed. To investigate a cholinergic activity of Lypd6, we studied a recombinant water-soluble variant of the human protein (ws-Lypd6) containing isolated “three-finger” LU-domain. Experiments at different nAChR subtypes expressed in Xenopus oocytes revealed the negative allosteric modulatory activity of ws-Lypd6. Ws-Lypd6 inhibited ACh-evoked currents at α3β4- and α7-nAChRs with IC50 of ∼35 and 10 μM, respectively, and the maximal amplitude of inhibition of 30–50%. EC50 of ACh at α3β4-nAChRs (∼30 μM) was not changed in the presence of 35 μM ws-Lypd6, while the maximal amplitude of ACh-evoked current was reduced by ∼20%. Ws-Lypd6 did not elicit currents through nAChRs in the absence of ACh. Application of 1 μM ws-Lypd6 significantly inhibited (up to ∼28%) choline-evoked current at α7-nAChRs in rat hippocampal slices. Similar to snake neurotoxin α-bungarotoxin, ws-Lypd6 suppressed the long-term potentiation (LTP) in mouse hippocampal slices. Colocalization of endogenous GPI-tethered Lypd6 with α3β4- and α7-nAChRs was detected in primary cortical and hippocampal neurons. Ws-Lypd6 interaction with the extracellular domain of α7-nAChR was modeled using the ensemble protein-protein docking protocol. The interaction of all three Lypd6 loops (“fingers”) with the entrance to the orthosteric ligand-binding site and the loop C of the primary receptor subunit was predicted. The results obtained allow us to consider Lypd6 as the endogenous negative modulator involved in the regulation of the cholinergic system in the brain.

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Molecular Dynamics Insight into the Lipid II Recognition by Type A Lantibiotics: Nisin, Epidermin, and Gallidermin

2021 · ARTICLE · en

Lanthionine-containing peptides (lantibiotics) have been considered as pharmaceutical candidates for decades, although their clinical application has been restricted. Most lantibiotics kill bacteria via targeting and segregating of the cell wall precursor—membrane-inserted lipid II molecule—in some cases accompanied by pores formation. Nisin-like lantibiotics specifically bind to pyrophosphate (PPi) moiety of lipid II with their structurally similar N-terminal thioether rings A and B. Although possessing higher pore-forming capability, nisin, in some cases, is 10-fold less efficient in vivo as compared to related epidermin and gallidermin peptides, differing just in a few amino acid residues within their target-binding regions. Here, using molecular dynamics simulations, we investigated atomistic details of intermolecular interactions between the truncated analogues of these peptides (residues 1–12) and lipid II mimic (dimethyl pyrophosphate, DMPPi). The peptides adopt similar conformation upon DMPPi binding with backbone amide protons orienting into a single center capturing PPi moiety via simultaneous formation of up to seven hydrogen bonds. Epidermin and gallidermin adopt the complex-forming conformation twice as frequent as nisin does, enhancing the binding by the lysine 4 side chain. Introduction of the similar residue to nisin in silico improves the binding, providing ideas for further design of prototypic antibiotics.

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All-d-Enantiomeric Peptide D3 Designed for Alzheimer's Disease Treatment Dynamically Interacts with Membrane-Bound Amyloid-β Precursors

2021 · ARTICLE · en

Alzheimer’s disease (AD) is a severe neurodegenerative pathology with no effective treatment known. Toxic amyloid-β peptide (Aβ) oligomers play a crucial role in AD pathogenesis. All-D-Enantiomeric peptide D3 and its derivatives were developed to disassemble and destroy cytotoxic Aβ aggregates. One of the D3-like compounds is approaching phase II clinical trials; however, high-resolution details of its disease-preventing or pharmacological actions are not completely clear. We demonstrate that peptide D3 stabilizing Aβ monomer dynamically interacts with the extracellular juxtamembrane region of a membrane-bound fragment of an amyloid precursor protein containing the Aβ sequence. MD simulations based on NMR measurement results suggest that D3 targets the amyloidogenic region, not compromising its α-helicity and preventing intermolecular hydrogen bonding, thus creating prerequisites for inhibition of early steps of Aβ conversion into β- conformation and its toxic oligomerization. An enhanced understanding of the D3 action molecular mechanism facilitates development of effective AD treatment and prevention strategies.

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Оценка взаимного влияния белок-мембрана для рецепторных тирозинкиназ в компьютерном эксперименте

2020 · CHAPTER · ru

Рецепторные тирозинкиназы — один из важнейших классов мембранных белков, отвечающих за регуляцию жизнедеятельности живых клеток. Среди большого числа рецепторов они обладают наиболее простой структурой — так, трансмембранный домен представлен одной альфа-спиралью. При этом он является функционально важным, поскольку изменение конформации формируемого димера отвечает за переход рецептора в активное/неактивное состояние. Известно, что липидное окружение оказывает влияние на работу таких белков, однако не все детали таких белок-липидных взаимодействий изучены. Помимо специфических взаимодействий с определёнными типами липидов, холестерином и, например, ганглиозидами наблюдают и неспецифические, поскольку в мембранных системах физико-химические параметры в значительной степени определяются липидным составом вблизи молекулы белка. При этом существуют противоположные гипотезы о том, что является движущей силой в формировании неоднородностей в мембране: сами молекулы липидов или встроенные в бислой мембранные белки. В настоящей работе для ответа на вопрос о взаимном влиянии белков и их липидного окружения применяли методы атомистического компьютерного моделирования: молекулярную динамику с последующим детальным анализом межмолекулярных контактов для выявления ключевых аминокислотных остатков, определяющих взаимодействия белок-липид. Показано, что число белок-липидных контактов зависит от конформации димерного состояния, а их распределение по монослоям несимметрично. Результаты работы помогут в понимании механизма передачи сигнала рецепторными тирозинкиназами и в поиске способов воздействия на эти рецепторы.

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Environmental and dynamic effects explain how nisin captures membrane-bound lipid II

2020 · ARTICLE · en

Antibiotics (AB) resistance is a major threat to global health, thus the development of novel AB classes is urgently needed. Lantibiotics (i.e. nisin) are natural compounds that effectively control bacterial populations, yet their clinical potential is very limited. Nisin targets membrane-embedded cell wall precursor — lipid II — via capturing its pyrophosphate group (PPi), which is unlikely to evolve, and thus represents a promising pharmaceutical target. Understanding of exact molecular mechanism of initial stages of membrane-bound lipid II recognition by water-soluble nisin is indispensable. Here, using molecular simulations, we demonstrate that the structure of lipid II is determined to a large extent by the surrounding water-lipid milieu. In contrast to the bulk solvent, in the bilayer only two conformational states remain capable of nisin binding. In these states PPi manifests a unique arrangement of hydrogen bond acceptors on the bilayer surface. Such a “pyrophosphate pharmacophore” cannot be formed by phospholipids, which explains high selectivity of nisin/lipid II recognition. Similarly, the “recognition module” of nisin, being rather flexible in water, adopts the only stable conformation in the presence of PPi analogue (which mimics the lipid II molecule). We establish the “energy of the pyrophosphate pharmacophore” approach, which effectively distinguishes nisin conformations that can form a complex with PPi. Finally, we propose a molecular model of nisin recognition module/lipid II complex in the bacterial membrane. These results will be employed for further study of lipid II targeting by antimicrobial (poly)cyclic peptides and for design of novel AB prototypes.

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Probing temperature and capsaicin-induced activation of TRPV1 channel via computationally guided point mutations in its pore and TRP domains

2020 · ARTICLE · en

In a recent computational study, we revealed some mechanistic aspects of TRPV1 (transient receptor potential channel 1) thermal activation and gating and proposed a set of probable functionally important residues — “hot spots” that have not been characterized experimentally yet. In this work, we analyzed TRPV1 point mutants G643A, I679A + A680G, and K688G/P combining molecular modeling, biochemistry, and electrophysiology. The substitution G643A reduced maximal conductivity that resulted in a normal response to moderate stimuli, but a relatively weak response to more intensive activation. I679A + A680G channel was severely toxic for oocytes most probably due to abnormally increased basal activity of the channel (“always open” gates). The replacement K688G presumably facilitated movements of TRP domain and disturbed its coupling to the pore, thus leading to spontaneous activation and enhanced desensitization of the channel. Finally, mutation K688P was suggested to impair TRP domain directed movement, and the mutated channel showed ~100-fold less sensitivity to the capsaicin, enhanced desensitization and weaker activation by the heat. Our results provide a better understanding of TRPV1 thermal and capsaicin-induced activation and gating. These observations provide a structural basis for understanding some aspects of TRPV1 channel functioning and depict potentially pathogenic mutations.

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Курсы (4)