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Hire Dr. Jonathan L.
Finland
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Computational Biophysicist | Clear, Compelling Scientific Writing

Profile Summary
Subject Matter Expertise
Services
Writing Technical Writing, General Proofreading & Editing
Research Scientific and Technical Research
Work Experience

University of Helsinki

- Present

Postdoctoral Researcher

University of Helsinki

January 2025 - Present

Postdoctoral Researcher

University of Helsinki

January 2024 - December 2024

Doctoral Researcher

University of Helsinki

September 2018 - December 2023

Education

University of Helsinki

- Present

Doctor of Philosophy

University of Helsinki

January 2019 - November 2024

Certifications
  • Certification details not provided.
Publications
JOURNAL ARTICLE
Assessment of amino acid charge states based on cryo-electron microscopy and molecular dynamics simulations of respiratory complex I @article{74cca24cde2b4e1db0df956a047a0699, title = "Assessment of amino acid charge states based on cryo-electron microscopy and molecular dynamics simulations of respiratory complex I", abstract = "The charge states of titratable amino acid residues play a key role in the function of membrane-bound bioenergetic proteins. However, determination of these charge states both through experimental and computational approaches is extremely challenging. Cryo-EM density maps can provide insights on the charge states of titratable amino acid residues. By performing classical atomistic molecular dynamics simulations on the high resolution cryo-EM structures of respiratory complex I from Yarrowia lipolytica, we analyze the conformational and charge states of a key acidic residue in its ND1 subunit, aspartic acid D203, which is also a mitochondrial disease mutation locus. We suggest that in the native state of respiratory complex I, D203 is negatively charged and maintains a stable hydrogen bond to a conserved arginine residue. Alternatively, upon conformational change in the turnover state of the enzyme, its sidechain attains a charge-neutral status. We discuss the implications of this analysis on the molecular mechanism of respiratory complex I.", keywords = "Charge transfer, Conformational dynamics, Coupling mechanism, Electrostatics, Proton pump, Protonation states, 1182 Biochemistry, cell and molecular biology", author = "Jonathan Lasham and Amina Djurabekova and Georgios Kolypetris and Volker Zickermann and Janet Vonck and Vivek Sharma", year = "2025", month = jan, day = "1", doi = "10.1016/j.bbabio.2024.149512", language = "English", volume = "1866", journal = "Biochimica et Biophysica Acta - Bioenergetics", issn = "0005-2728", publisher = "Elsevier B.V.", number = "1", } . Biochimica et Biophysica Acta - Bioenergetics.
Long-range electron proton coupling in respiratory complex I — insights from molecular simulations of the quinone chamber and antiporter-like subunits @article{e19ef3923e254b73bea8807fcdb4e27c, title = "Long-range electron proton coupling in respiratory complex I — insights from molecular simulations of the quinone chamber and antiporter-like subunits", abstract = "Respiratory complex I is a redox-driven proton pump. Several high-resolution structures of complex I have been determined providing important information about the putative proton transfer paths and conformational transitions that may occur during catalysis. However, how redox energy is coupled to the pumping of protons remains unclear. In this article, we review biochemical, structural and molecular simulation data on complex I and discuss several coupling models, including the key unresolved mechanistic questions. Focusing both on the quinone-reductase domain as well as the proton-pumping membrane-bound domain of complex I, we discuss a molecular mechanism of proton pumping that satisfies most experimental and theoretical constraints. We suggest that protonation reactions play an important role not only in catalysis, but also in the physiologically-relevant active/deactive transition of complex I.", keywords = "114 Physical sciences, 1182 Biochemistry, cell and molecular biology", author = "Amina Djurabekova and Jonathan Lasham and Oleksii Zdorevskyi and Volker Zickermann and Vivek Sharma", year = "2024", month = apr, doi = "10.1042/BCJ20240009", language = "English", volume = "481", pages = "499–514", journal = "Biochemical Journal", issn = "0264-6021", publisher = "Portland Press Ltd.", number = "7", } . Biochemical Journal.
Role of Protonation States in the Stability of Molecular Dynamics Simulations of High-Resolution Membrane Protein Structures @article{3ea897f8abbf458586487c6448d32bc5, title = "Role of Protonation States in the Stability of Molecular Dynamics Simulations of High-Resolution Membrane Protein Structures", abstract = "Classical molecular dynamics (MD) simulations provide unmatched spatial and time resolution of protein structure and function. However, the accuracy of MD simulations often depends on the quality of force field parameters and the time scale of sampling. Another limitation of conventional MD simulations is that the protonation states of titratable amino acid residues remain fixed during simulations, even though protonation state changes coupled to conformational dynamics are central to protein function. Due to the uncertainty in selecting protonation states, classical MD simulations are sometimes performed with all amino acids modeled in their standard charged states at pH 7. Here, we performed and analyzed classical MD simulations on high-resolution cryo-EM structures of two large membrane proteins that transfer protons by catalyzing protonation/deprotonation reactions. In simulations performed with titratable amino acids modeled in their standard protonation (charged) states, the structure diverges far from its starting conformation. In comparison, MD simulations performed with predetermined protonation states of amino acid residues reproduce the structural conformation, protein hydration, and protein-water and protein-protein interactions of the structure much better. The results support the notion that it is crucial to perform basic protonation state calculations, especially on structures where protonation changes play an important functional role, prior to the launch of any conventional MD simulations. Furthermore, the combined approach of fast protonation state prediction and MD simulations can provide valuable information about the charge states of amino acids in the cryo-EM sample. Even though accurate prediction of protonation states in proteinaceous environments currently remains a challenge, we introduce an approach of combining pK a prediction with cryo-EM density map analysis that helps in improving not only the protonation state predictions but also the atomic modeling of density data.", keywords = "1182 Biochemistry, cell and molecular biology, 114 Physical sciences", author = "Jonathan Lasham and Amina Djurabekova and Volker Zickermann and Janet Vonck and Vivek Sharma", year = "2024", month = mar, day = "2", doi = "10.1021/acs.jpcb.3c07421", language = "English", volume = "128", pages = "2304–2316", journal = "Journal of Physical Chemistry B", issn = "1520-6106", publisher = "American Chemical Society", number = "10", } . Journal of Physical Chemistry B.
Nanobody engineering for SARS-CoV-2 neutralization and detection @article{a779cbd166ea4566b3e0efa8eae2e9b7, title = "Nanobody engineering for SARS-CoV-2 neutralization and detection", abstract = "In response to the ongoing COVID-19 pandemic, the quest for coronavirus inhibitors has inspired research on a variety of small proteins beyond conventional antibodies, including robust single-domain antibody fragments, i.e., {"}nanobodies.{"} Here, we explore the potential of nanobody engineering in the development of antivirals and diagnostic tools. Through fusion of nanobody domains that target distinct binding sites, we engineered multimodular nanobody constructs that neutralize wild-type SARS-CoV-2 and the Alpha and Delta variants at high potency, with IC50 values as low as 50 pM. Despite simultaneous binding to distinct epitopes, Beta and Omicron variants were more resistant to neutralization by the multimodular nanobodies, which highlights the importance of accounting for antigenic drift in the design of biologics. To further explore the applications of nanobody engineering in outbreak management, we present an assay based on fusions of nanobodies with fragments of NanoLuc luciferase that can detect sub-nanomolar quantities of the SARS-CoV-2 spike protein in a single step. Our work showcases the potential of nanobody engineering to combat emerging infectious diseases.IMPORTANCENanobodies, small protein binders derived from the camelid antibody, are highly potent inhibitors of respiratory viruses that offer several advantages over conventional antibodies as candidates for specific therapies, including high stability and low production costs. In this work, we leverage the unique properties of nanobodies and apply them as building blocks for new therapeutic and diagnostic tools. We report ultra-potent SARS-CoV-2 inhibition by engineered nanobodies comprising multiple modules in structure-guided combinations and develop nanobodies that carry signal molecules, allowing rapid detection of the SARS-CoV-2 spike protein. Our results highlight the potential of engineered nanobodies in the development of effective countermeasures, both therapeutic and diagnostic, to manage outbreaks of emerging viruses.Nanobodies, small protein binders derived from the camelid antibody, are highly potent inhibitors of respiratory viruses that offer several advantages over conventional antibodies as candidates for specific therapies, including high stability and low production costs. In this work, we leverage the unique properties of nanobodies and apply them as building blocks for new therapeutic and diagnostic tools. We report ultra-potent SARS-CoV-2 inhibition by engineered nanobodies comprising multiple modules in structure-guided combinations and develop nanobodies that carry signal molecules, allowing rapid detection of the SARS-CoV-2 spike protein. Our results highlight the potential of engineered nanobodies in the development of effective countermeasures, both therapeutic and diagnostic, to manage outbreaks of emerging viruses.", keywords = "SARS-CoV-2, Diagnostics, Nanobody, Protein engineering, Virus neutralization, 11832 Microbiology and virology", author = "Liina Hannula and Suvi Kuivanen and Jonathan Lasham and Ravi Kant and Lauri Kareinen and Mariia Bogacheva and Tomas Strandin and Tarja Sironen and Jussi Hepojoki and Vivek Sharma and Petri Saviranta and Anja Kipar and Olli Vapalahti and Huiskonen, {Juha T.} and Ilona Rissanen", year = "2024", month = feb, doi = "10.1128/spectrum.04199-22", language = "English", volume = "12", journal = "Microbiology Spectrum", issn = "2165-0497", publisher = "ASM Press", number = "4", } . Microbiology Spectrum.
Horizontal proton transfer across the antiporter-like subunits in mitochondrial respiratory complex I @article{24d1496c8d364cd099e293224c42a6cb, title = "Horizontal proton transfer across the antiporter-like subunits in mitochondrial respiratory complex I", abstract = "Respiratory complex I is a redox-driven proton pump contributing to about 40% of total proton motive force required for mitochondrial ATP generation. Recent high-resolution cryo-EM structural data revealed the positions of several water molecules in the membrane domain of the large enzyme complex. However, it remains unclear how protons flow in the membrane-bound antiporter-like subunits of complex I. Here, we performed multiscale computer simulations on high-resolution structural data to model explicit proton transfer processes in the ND2 subunit of complex I. Our results show protons can travel the entire width of antiporter-like subunits, including at the subunit-subunit interface, parallel to the membrane. We identify a previously unrecognized role of conserved tyrosine residues in catalyzing horizontal proton transfer, and that long-range electrostatic effects assist in reducing energetic barriers of proton transfer dynamics. Results from our simulations warrant a revision in several prevailing proton pumping models of respiratory complex I.", keywords = "Coupling mechanism, Escherichia-coli, 1182 Biochemistry, cell and molecular biology", author = "Oleksii Zdorevskyi and Amina Djurabekova and Jonathan Lasham and Vivek Sharma", year = "2023", month = may, day = "10", doi = "10.1039/d3sc01427d", language = "English", volume = "14", pages = "6309--6318", journal = "Chemical Science", issn = "2041-6520", publisher = "Royal Society of Chemistry", number = "23", } . Chemical Science.
Tunnel dynamics of quinone derivatives and its coupling to protein conformational rearrangements in respiratory complex I @article{8f87619bc1094c46acff2d38ad9af516, title = "Tunnel dynamics of quinone derivatives and its coupling to protein conformational rearrangements in respiratory complex I", abstract = "Respiratory complex I in mitochondria and bacteria catalyzes the transfer of electrons from NADH to quinone (Q). The free energy available from the reaction is used to pump protons and to establish a membrane proton electrochemical gradient, which drives ATP synthesis. Even though several high-resolution structures of complex I have been resolved, how Q reduction is linked with proton pumping, remains unknown. Here, microsecond long molecular dynamics (MD) simulations were performed on Yarrowia lipolytica complex I structures where Q molecules have been resolved in the similar to 30 angstrom long Q tunnel. MD simulations of several different redox/protonation states of Q reveal the coupling between the Q dynamics and the restructuring of conserved loops and ion pairs. Oxidized quinone stabilizes towards the N2 FeS cluster, a binding mode not previously described in Yarrowia lipolytica complex I structures. On the other hand, reduced (and protonated) species tend to diffuse towards the Q binding sites closer to the tunnel entrance. Mechanistic and physiological relevance of these results are discussed.", keywords = "1182 Biochemistry, cell and molecular biology, Bioenergetics, Electron transfer, Molecular dynamics simulations, Proton pumping, Semiquinone", author = "Jonathan Lasham and Outi Haapanen and Volker Zickermann and Vivek Sharma", year = "2023", month = apr, day = "1", doi = "10.1016/j.bbabio.2022.148951", language = "English", volume = "1864", journal = "Biochimica et Biophysica Acta. Bioenergetics", issn = "0005-2728", publisher = "Elsevier B.V.", number = "2", } . Biochimica et Biophysica Acta. Bioenergetics.
Jonathan Lasham, Oleksii Zdorevskyi, Amina Djurabekova, Vivek Sharma (2023). Horizontal proton transfer across the antiporter-like subunits in mitochondrial respiratory complex I . Chemical Science.
Diverse reaction behaviors of artificial ubiquinones in mitochondrial respiratory complex I @article{91662359593c403eaf73c52c79507886, title = "Diverse reaction behaviors of artificial ubiquinones in mitochondrial respiratory complex I", abstract = "The ubiquinone (UQ) reduction step catalyzed by NADH-UQ oxidoreductase (mitochondrial respiratory complex I) is key to triggering proton translocation across the inner mitochondrial membrane. Structural studies have identified a long, narrow, UQ-accessing tunnel within the enzyme. We previously demonstrated that synthetic oversized UQs, which are unlikely to transit this narrow tunnel, are catalytically reduced by native complex I embedded in submitochondrial particles but not by the isolated enzyme. To explain this contradiction, we hypothesized that access of oversized UQs to the reaction site is obstructed in the isolated enzyme because their access route is altered following detergent solubilization from the inner mitochondrial membrane. In the present study, we investigated this using two pairs of photoreactive UQs (pUQ(m-1)/pUQ(p-1) and pUQ(m-2)/pUQ(p-2)), with each pair having the same chemical properties except for a similar to 1.0 angstrom difference in side-chain widths. Despite this subtle difference, reduction of the wider pUQs by the isolated complex was significantly slower than of the narrower pUQs, but both were similarly reduced by the native enzyme. In addition, photoaffinity-labeling experiments using the four [I-125]pUQs demonstrated that their side chains predominantly label the ND1 subunit with both enzymes but at different regions around the tunnel. Finally, we show that the suppressive effects of different types of inhibitors on the labeling significantly changed depending on [I-125]pUQs used, indicating that [I-125]pUQs and these inhibitors do not necessarily share a common binding cavity. Altogether, we conclude that the reaction behaviors of pUQs cannot be simply explained by the canonical UQ tunnel model.", keywords = "MOLECULAR-DYNAMICS, STRUCTURAL DYNAMICS, COUPLING MECHANISM, CRYSTAL-STRUCTURE, REACTION SITE, PROTON PUMP, OXIDOREDUCTASE, IDENTIFICATION, INHIBITORS, BINDING, 1182 Biochemistry, cell and molecular biology", author = "Shinpei Uno and Takahiro Masuya and Oleksii Zdorevskyi and Ryo Ikunishi and Kyoko Shinzawa-Itoh and Jonathan Lasham and Vivek Sharma and Masatoshi Murai and Hideto Miyoshi", year = "2022", month = jul, doi = "10.1016/j.jbc.2022.102075", language = "English", volume = "298", journal = "Journal of Biological Chemistry", issn = "0021-9258", publisher = "American Society for Biochemistry and Molecular Biology Inc.", number = "7", } . Journal of Biological Chemistry.
Jonathan Lasham, Kristian Parey, Deryck J. Mills, Amina Djurabekova, Outi Haapanen, Etienne Galemou Yoga, Hao Xie, Werner Kühlbrandt, Vivek Sharma, Janet Vonck, et al.(2021). High-resolution structure and dynamics of mitochondrial complex I—Insights into the proton pumping mechanism . Science Advances. 7. (46). American Association for the Advancement of Science ({AAAS})
High-resolution structure and dynamics of mitochondrial complex I-Insights into the proton pumping mechanism @article{2111661989624d95a8d536a79d16498c, title = "High-resolution structure and dynamics of mitochondrial complex I-Insights into the proton pumping mechanism", abstract = "Mitochondrial NADH:ubiquinone oxidoreductase (complex I) is a 1-MDa membrane protein complex with a central role in energy metabolism. Redox-driven proton translocation by complex I contributes substantially to the proton motive force that drives ATP synthase. Several structures of complex I from bacteria and mitochondria have been determined, but its catalytic mechanism has remained controversial. We here present the cryo-EM structure of complex I from Yarrowia lipolytica at 2.1-angstrom resolution, which reveals the positions of more than 1600 protein-bound water molecules, of which similar to 100 are located in putative proton translocation pathways. Another structure of the same complex under steady-state activity conditions at 3.4-angstrom resolution indicates conformational transitions that we associate with proton injection into the central hydrophilic axis. By combining high-resolution structural data with site-directed mutagenesis and large-scale molecular dynamic simulations, we define details of the proton translocation pathways and offer insights into the redox-coupled proton pumping mechanism of complex I.", keywords = "MOLECULAR-DYNAMICS, FORCE-FIELD, CRYSTAL-STRUCTURE, CRYO-EM, NADH, SUBUNIT, STOICHIOMETRY, VISUALIZATION, ORIENTATION, TRANSITION, 114 Physical sciences", author = "Kristian Parey and Jonathan Lasham and Mills, {Deryck J.} and Amina Djurabekova and Outi Haapanen and Yoga, {Etienne Galemou} and Hao Xie and Werner Kuhlbrandt and Vivek Sharma and Janet Vonck and Volker Zickermann", year = "2021", month = nov, doi = "10.1126/sciadv.abj3221", language = "English", volume = "7", journal = "Science Advances", issn = "2375-2548", publisher = "American Association for the Advancement of Science (AAAS)", number = "46", } . Science Advances.
Hydrogen bonding rearrangement by a mitochondrial disease mutation in cytochrome bc1 perturbs heme bH redox potential and spin state @article{9c2f20fde51240e2b412e481dc649ef3, title = "Hydrogen bonding rearrangement by a mitochondrial disease mutation in cytochrome bc1 perturbs heme bH redox potential and spin state", abstract = "Hemes are common elements of biological redox cofactor chains involved in rapid electron transfer. While the redox properties of hemes and the stability of the spin state are recognized as key determinants of their function, understanding the molecular basis of control of these properties is challenging. Here, benefiting from the effects of one mitochondrial disease-related point mutation in cytochrome b, we identify a dual role of hydrogen bonding (H-bond) to the propionate group of heme bH of cytochrome bc1, a common component of energy-conserving systems. We found that replacing conserved glycine with serine in the vicinity of heme bH caused stabilization of this bond, which not only increased the redox potential of the heme but also induced structural and energetic changes in interactions between Fe ion and axial histidine ligands. The latter led to a reversible spin conversion of the oxidized Fe from 1/2 to 5/2, an effect that potentially reduces the electron transfer rate between the heme and its redox partners. We thus propose that H-bond to the propionate group and heme-protein packing contribute to the fine-tuning of the redox potential of heme and maintaining its proper spin state. A subtle balance is needed between these two contributions: While increasing the H-bond stability raises the heme potential, the extent of increase must be limited to maintain the low spin and diamagnetic form of heme. This principle might apply to other native heme proteins and can be exploited in engineering of artificial hemecontaining protein maquettes.", keywords = "114 Physical sciences, mitochondrial dysfunction, electron paramagnetic resonance, molecular dynamics simulations, density functional theory, electron transfer, RHODOBACTER-CAPSULATUS, UBIQUINOL-CYTOCHROME-C2 OXIDOREDUCTASE, CORRELATION-ENERGY, ELECTRON-TRANSFER, BIS-HISTIDINE, COMPLEX-III, Q(O) SITE, DYNAMICS, BC(1), INTERFACE", author = "Patryk Kuleta and Jonathan Lasham and Marcin Sarewicz and Iwona Ekiert and Vivek Sharma and Robert Ekiert and Artur Osyczka", year = "2021", month = aug, day = "17", doi = "10.1073/pnas.2026169118", language = "English", volume = "118", journal = "Proceedings of the National Academy of Sciences of the United States of America", issn = "0027-8424", publisher = "National Academy of Sciences", number = "33", } . Proceedings of the National Academy of Sciences of the United States of America.
Jonathan Lasham, Patryk Kuleta, Marcin Sarewicz, Iwona Ekiert, Vivek Sharma, Robert Ekiert, Artur Osyczka(2021). Hydrogen bonding rearrangement by a mitochondrial disease mutation in cytochrome bc 1 perturbs heme b H redox potential and spin state . Proceedings of the National Academy of Sciences. 118. (33). Proceedings of the National Academy of Sciences
Oversized ubiquinones as molecular probes for structural dynamics of the ubiquinone reaction site in mitochondrial respiratory complex I @article{71656a7414394e9ba9a421446a596fbb, title = "Oversized ubiquinones as molecular probes for structural dynamics of the ubiquinone reaction site in mitochondrial respiratory complex I", abstract = "NADH-quinone oxidoreductase (complex I) couples electron transfer from NADH to quinone with proton translocation across the membrane. Quinone reduction is a key step for energy transmission from the site of quinone reduction to the remotely located proton-pumping machinery of the enzyme. Although structural biology studies have proposed the existence of a long and narrow quinone-access channel, the physiological relevance of this channel remains debatable. We investigated here whether complex I in bovine heart submitochondrial particles (SMPs) can catalytically reduce a series of oversized ubiquinones (OS-UQs), which are highly unlikely to transit the narrow channel because their side chain includes a bulky ?block? that is ?13 ? across. We found that some OS-UQs function as efficient electron acceptors from complex I, accepting electrons with an efficiency comparable with ubiquinone-2. The catalytic reduction and proton translocation coupled with this reduction were completely inhibited by different quinone-site inhibitors, indicating that the reduction of OS-UQs takes place at the physiological reaction site for ubiquinone. Notably, the proton-translocating efficiencies of OS-UQs significantly varied depending on their side-chain structures, suggesting that the reaction characteristics of OS-UQs affect the predicted structural changes of the quinone reaction site required for triggering proton translocation. These results are difficult to reconcile with the current channel model; rather, the access path for ubiquinone may be open to allow OS-UQs to access the reaction site. Nevertheless, contrary to the observations in SMPs, OS-UQs were not catalytically reduced by isolated complex I reconstituted into liposomes. We discuss possible reasons for these contradictory results.", keywords = "bioenergetics, mitochondria, complex I, ubiquinone, chemical biology, respiratory chain, proton pump, PINPOINT CHEMICAL-MODIFICATION, 49 KDA, CRYSTAL-STRUCTURE, INNER MEMBRANE, PROTON PUMP, NADH, REDUCTION, OXIDOREDUCTASE, MECHANISM, BINDING, 1182 Biochemistry, cell and molecular biology, 114 Physical sciences", author = "Shinpei Uno and Takahiro Masuya and Kyoko Shinzawa-Itoh and Jonathan Lasham and Outi Haapanen and Tomoo Shiba and Inaoka, {Daniel Ken} and Vivek Sharma and Masatoshi Murai and Hideto Miyoshi", year = "2020", month = feb, day = "21", doi = "10.1074/jbc.RA119.012347", language = "English", volume = "295", pages = "2449--2463", journal = "Journal of Biological Chemistry", issn = "0021-9258", publisher = "American Society for Biochemistry and Molecular Biology Inc.", number = "8", } . Journal of Biological Chemistry.
CONFERENCE ABSTRACT
Predictive Insights into Protonation States of Key Residues in Bioenergetic Proteins Using Conventional and Constant-pH MD Simulations @article{a4cd5367212e4a0095d1cdcc9e0a25a1, title = "Predictive Insights into Protonation States of Key Residues in Bioenergetic Proteins Using Conventional and Constant-pH MD Simulations", keywords = "114 Physical sciences, 1182 Biochemistry, cell and molecular biology", author = "Jonathan Lasham and Vivek Sharma", year = "2024", month = sep, day = "1", doi = "10.1016/j.bbabio.2024.149327", language = "English", volume = "1865", pages = "83--83", journal = "Biochimica et Biophysica Acta. Bioenergetics", issn = "0005-2728", publisher = "Elsevier B.V.", number = "Supplement", note = "22nd European Bioenergetics Conference, EBEC 2024 ; Conference date: 26-08-2024 Through 31-08-2024", url = "https://www.ebec2024.org/", } . Biochimica et Biophysica Acta. Bioenergetics.
(S6.P3) New insights into role of hydrogen bonding on the redox properties of hemes and proton transfer in cytochrome bc1 @article{2ee2198a18cd451ea094fbba17b4ec88, title = "(S6.P3) New insights into role of hydrogen bonding on the redox properties of hemes and proton transfer in cytochrome bc1", keywords = "114 Physical sciences", author = "Patryk Kuleta and Robert Ekiert and Jonathan Lasham and Arkadiusz Borek and Anna Wojcik-Augustyn and Vivek Sharma and Artur Osyczka", year = "2022", month = sep, doi = "10.1016/j.bbabio.2022.148745", language = "English", volume = "1863", pages = "50--51", journal = "Biochimica et Biophysica Acta. Bioenergetics", issn = "0005-2728", publisher = "Elsevier B.V.", } . Biochimica et Biophysica Acta. Bioenergetics.
Jonathan Lasham, Outi Haapanen, Volker Zickermann, Vivek Sharma(2022). Molecular dynamics simulations reveal the coupling of quinone dynamics to protein conformational changes in respiratory complex I . Biochimica et Biophysica Acta. Bioenergetics. 1863. p. 17. Elsevier B.V.
DISSERTATION THESIS
The function and dysfunction of respiratory complexes studied by computational methods @phdthesis{59312f79555f4456826d80c64be38daf, title = "The function and dysfunction of respiratory complexes studied by computational methods", abstract = "Cellular respiration produces the energy that cells need to function, in the chemical form of adenosine triphosphate (ATP). In eukaryotes, it is produced by a series of redox reactions that take place in mitochondria, known as the electron transport chain (ETC). These redox reactions happen in large, membrane-bound enzymes known as respiratory complexes.The first and largest respiratory enzyme, complex I, binds its substrate quinone in a ca. 35 {\AA}-long cavity, where it is reduced to quinol through a set of redox reactions. These redox reactions are coupled with the pumping of 4 protons up to 200 {\AA} away. Quinol is then transferred to complex III, which again takes part in a redox process known as the Q cycle, pumping 4 more protons into the intermembrane space. It is the formation of a proton gradient that drives the synthesis of ATP by ATP synthase. Disruptions in the ETC in the form of point mutations can cause mitochondrial diseases, which can have a devastating impact on human health. In order to study the molecular basis of these diseases, we must first understand the healthy functioning of respiratory enzymes.In this thesis, computational methods, including molecular dynamics (MD) simulations, are exploited to better understand the function of respiratory complex I. The dynamics of quinone and its analogs are studied, revealing key coupling mechanisms between protein and ligand dynamics in the quinone tunnel. The dynamics of syntheticallymodified quinones are also discussed, challenging the notion of the quinone tunnel being the only route for substrate exchange to take place. Using high-resolution structural data, potential signaling mechanisms in the coupling of the redox reaction and proton pumping are presented. Large-scale MD simulations also show water dynamics within the membrane arm of complex I and suggest that the pathways of proton pumping could be different from the previous consensus.Finally, the dysfunction of both respiratory complexes I and III is examined, with many key residues being identified that are known to be related to mitochondrial diseases. How these residues impact the molecular mechanism is speculated upon. In complex III, a disease-causing mutation has been studied, and using a combination of MD and density functional theory (DFT) calculations, the subtle effects of the mutation on the heme bH redox center of the enzyme are elucidated.", keywords = "biophysics, biophysics, biophysics, 114 Physical sciences, 116 Chemical sciences, 1182 Biochemistry, cell and molecular biology", author = "Jonathan Lasham", year = "2023", month = nov, day = "20", language = "English", isbn = "978-951-51-9524-1", series = "Dissertationes Universitatis Helsingiensis", publisher = "University of Helsinki", number = "93/2023", address = "Finland", school = "University of Helsinki", } . Dissertationes Universitatis Helsingiensis.