Umeå University's logo

umu.sePublications
Change search
Refine search result
1 - 14 of 14
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1. Arbeitman, Claudia R.
    et al.
    Rojas, Pablo
    Ojeda-May, Pedro
    Umeå University, Faculty of Science and Technology, High Performance Computing Center North (HPC2N). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Garcia, Martin E.
    The SARS-CoV-2 spike protein is vulnerable to moderate electric fields2021In: Nature Communications, E-ISSN 2041-1723, Vol. 12, no 1, article id 5407Article in journal (Refereed)
    Abstract [en]

    Most of the ongoing projects aimed at the development of specific therapies and vaccines against COVID-19 use the SARS-CoV-2 spike (S) protein as the main target. The binding of the spike protein with the ACE2 receptor (ACE2) of the host cell constitutes the first and key step for virus entry. During this process, the receptor binding domain (RBD) of the S protein plays an essential role, since it contains the receptor binding motif (RBM), responsible for the docking to the receptor. So far, mostly biochemical methods are being tested in order to prevent binding of the virus to ACE2. Here we show, with the help of atomistic simulations, that external electric fields of easily achievable and moderate strengths can dramatically destabilise the S protein, inducing long-lasting structural damage. One striking field-induced conformational change occurs at the level of the recognition loop L3 of the RBD where two parallel beta sheets, believed to be responsible for a high affinity to ACE2, undergo a change into an unstructured coil, which exhibits almost no binding possibilities to the ACE2 receptor. We also show that these severe structural changes upon electric-field application also occur in the mutant RBDs corresponding to the variants of concern (VOC) B.1.1.7 (UK), B.1.351 (South Africa) and P.1 (Brazil). Remarkably, while the structural flexibility of S allows the virus to improve its probability of entering the cell, it is also the origin of the surprising vulnerability of S upon application of electric fields of strengths at least two orders of magnitude smaller than those required for damaging most proteins. Our findings suggest the existence of a clean physical method to weaken the SARS-CoV-2 virus without further biochemical processing. Moreover, the effect could be used for infection prevention purposes and also to develop technologies for in-vitro structural manipulation of S. Since the method is largely unspecific, it can be suitable for application to other mutations in S, to other proteins of SARS-CoV-2 and in general to membrane proteins of other virus types.

    Download full text (pdf)
    fulltext
  • 2.
    Bispo, João
    et al.
    University of Porto, Portugal.
    Barbosa, Jorge G.
    University of Porto, Portugal.
    Silva, Pedro Filipe
    University of Porto, Portugal.
    Morales, Cristian
    BSC, Spain.
    Myllykoski, Mirko
    Umeå University, Faculty of Science and Technology, High Performance Computing Center North (HPC2N).
    Ojeda-May, Pedro
    Umeå University, Faculty of Science and Technology, High Performance Computing Center North (HPC2N).
    Bialczak, Milosz
    WCSS, Poland.
    Uchronski, Mariusz
    WCSS, Poland.
    Wlodarczyk, Adam
    WCSS, Poland.
    Wauligmann, Peter
    HLRS, Germany.
    Krishnasamy, Ezhilmathi
    University of Luxembourg, Luxembourg.
    Varrette, Sebastien
    University of Luxembourg, Luxembourg.
    Lührs, Sebastian
    JSC, Germany.
    Shoukourian, Hayk
    LRZ, Germany.
    Best Practice Guide: Modern Accelerators2021Report (Other academic)
  • 3.
    Dinh, Van Minh
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Khokarale, Santosh Govind
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ojeda-May, Pedro
    Umeå University, Faculty of Science and Technology, High Performance Computing Center North (HPC2N).
    Sparrman, Tobias
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Irgum, Knut
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Mikkola, Jyri-Pekka
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Industrial Chemistry & Reaction Engineering, Department of Chemical Engineering, Process Chemistry Centre, Åbo Akademi University, ÅboTurku, Finland.
    Ionic liquid strategy for chitosan production from chitin and molecular insights2024In: RSC Sustainability, E-ISSN 2753-8125, Vol. 2, no 4, p. 1154-1164Article in journal (Refereed)
    Abstract [en]

    To produce chitosan is an interesting research. Chitosan is an important polysaccharide in terms of its various applications in industries and is produced from chitin, an abundant biopolymer in crustacean shell biomass wastes. Traditional processes for chitosan manufacture are commonly based on highly concentrated alkaline or acid solutions which are, however, severely eroding and harmful to the environment. In this study, we have described a ‘greener’ method using 1-ethyl-3-methylimidazolium acetate, [Emim][OAc] ionic liquid (IL), for decrystallization of shrimp crystalline chitin flakes followed by a microwave-mediated NaOH or tetrabutylammonium hydroxide, [TBA][OH], solution-based deacetylation for chitosan production. The decrease in crystallinity in IL pre-treated chitin was confirmed by XRD and SEM analysis which subsequently benefited chitosan production with up to 85% degree of deacetylation (%DDA) in shorter time periods (1-2 hours) and lower alkaline concentrations (20-40%). The %DDA in chitin/chitosan was estimated via FT-IR and NMR analysis. Notably, we could regenerate the ionic liquids: in case of [Emim][OAc] 97 wt.% and in case of [TBA][OH] 83 wt.% could be reused. Roles of ionic liquids in the process were discussed. Molecular dynamics (MD) simulations showed the roles of [TBA]+ cations in the molecular driving forces of [TBA][OH]-induced deacetylation mechanism. The strategy promises a sustainable and milder reaction approach to the existing highly corrosive alkaline- or acid-involved processes for chitosan production.

    Download full text (pdf)
    fulltext
  • 4.
    Dulko-Smith, Beata
    et al.
    Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, Texas, USA.
    Ojeda-May, Pedro
    Umeå University, Faculty of Science and Technology, High Performance Computing Center North (HPC2N).
    Ådén, Jörgen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wolf-Watz, Magnus
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nam, Kwangho
    Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, Texas, USA.
    Mechanistic basis for a connection between the catalytic step and slow opening dynamics of adenylate kinase2023In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 63, no 5, p. 1556-1569Article in journal (Refereed)
    Abstract [en]

    Escherichia coli adenylate kinase (AdK) is a small, monomeric enzyme that synchronizes the catalytic step with the enzyme’s conformational dynamics to optimize a phosphoryl transfer reaction and the subsequent release of the product. Guided by experimental measurements of low catalytic activity in seven single-point mutation AdK variants (K13Q, R36A, R88A, R123A, R156K, R167A, and D158A), we utilized classical mechanical simulations to probe mutant dynamics linked to product release, and quantum mechanical and molecular mechanical calculations to compute a free energy barrier for the catalytic event. The goal was to establish a mechanistic connection between the two activities. Our calculations of the free energy barriers in AdK variants were in line with those from experiments, and conformational dynamics consistently demonstrated an enhanced tendency toward enzyme opening. This indicates that the catalytic residues in the wild-type AdK serve a dual role in this enzyme’s function─one to lower the energy barrier for the phosphoryl transfer reaction and another to delay enzyme opening, maintaining it in a catalytically active, closed conformation for long enough to enable the subsequent chemical step. Our study also discovers that while each catalytic residue individually contributes to facilitating the catalysis, R36, R123, R156, R167, and D158 are organized in a tightly coordinated interaction network and collectively modulate AdK’s conformational transitions. Unlike the existing notion of product release being rate-limiting, our results suggest a mechanistic interconnection between the chemical step and the enzyme’s conformational dynamics acting as the bottleneck of the catalytic process. Our results also suggest that the enzyme’s active site has evolved to optimize the chemical reaction step while slowing down the overall opening dynamics of the enzyme.

  • 5.
    Lipskij, Alexander
    et al.
    Theoretical Physics and Center of Interdisciplinary Nanostructure Science and Technology, Universität Kassel, Kassel, Germany.
    Arbeitman, Claudia
    Theoretical Physics and Center of Interdisciplinary Nanostructure Science and Technology, Universität Kassel, Kassel, Germany; CONICET Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina; GIBIO-Universidad Tecnológica Nacional-Facultad Regional Buenos Aires, Buenos Aires, Argentina.
    Rojas, Pablo
    Theoretical Physics and Center of Interdisciplinary Nanostructure Science and Technology, Universität Kassel, Kassel, Germany.
    Ojeda-May, Pedro
    Umeå University, Faculty of Science and Technology, High Performance Computing Center North (HPC2N).
    Garcia, Martin E.
    Theoretical Physics and Center of Interdisciplinary Nanostructure Science and Technology, Universität Kassel, Kassel, Germany.
    Dramatic differences between the structural susceptibility of the S1 pre- and S2 postfusion states of the SARS-CoV-2 spike protein to external electric fields revealed by molecular dynamics simulations2023In: Viruses, E-ISSN 1999-4915, Vol. 15, no 12, p. 2405-2419Article in journal (Refereed)
    Abstract [en]

    In its prefusion state, the SARS-CoV-2 spike protein (similarly to other class I viral fusion proteins) is metastable, which is considered to be an important feature for optimizing or regulating its functions. After the binding process of its S1 subunit (S1) with ACE2, the spike protein (S) undergoes a dramatic conformational change where S1 splits from the S2 subunit, which then penetrates the membrane of the host cell, promoting the fusion of the viral and cell membranes. This results in the infection of the host cell. In a previous work, we showed—using large-scale molecular dynamics simulations—that the application of external electric fields (EFs) induces drastic changes and damage in the receptor-binding domain (RBD) of the wild-type spike protein, as well of the Alpha, Beta, and Gamma variants, leaving a structure which cannot be recognized anymore by ACE2. In this work, we first extend the study to the Delta and Omicron variants and confirm the high sensitivity and extreme vulnerability of the RBD of the prefusion state of S to moderate EF (as weak as 104 V/m), but, more importantly, we also show that, in contrast, the S2 subunit of the postfusion state of the spike protein does not suffer structural damage even if electric field intensities four orders of magnitude higher are applied. These results provide a solid scientific basis to confirm the connection between the prefusion-state metastability of the SARS-CoV-2 spike protein and its susceptibility to be damaged by EF. After the virus docks to the ACE2 receptor, the stable and robust postfusion conformation develops, which exhibits a similar resistance to EF (damage threshold higher than 108 V/m) like most globular proteins.

    Download full text (pdf)
    fulltext
  • 6.
    Ojeda-May, Pedro
    Umeå University, Faculty of Science and Technology, High Performance Computing Center North (HPC2N).
    Exploring the dynamics of holo-shikimate kinase through molecular mechanics2023In: Biophysica, ISSN 2673-4125, Vol. 3, no 3, p. 463-475Article in journal (Refereed)
    Abstract [en]

    Understanding the connection between local and global dynamics can provide valuable insights into enzymatic function and may contribute to the development of novel strategies for enzyme modulation. In this work, we investigated the dynamics at both the global and local (active site) levels of Shikimate Kinase (SK) through microsecond time-scale molecular dynamics (MD) simulations of the holoenzyme in the product state. Our focus was on the wild-type (WT) enzyme and two mutants (R116A and R116K) which are known for their reduced catalytic activity. Through exploring the dynamics of these variants, we gained insights into the role of residue R116 and its contribution to overall SK dynamics. We argue that the connection between local and global dynamics can be attributed to local frustration near the mutated residue which perturbs the global protein dynamics.

    Download full text (pdf)
    fulltext
  • 7.
    Ojeda-May, Pedro
    Umeå University, Faculty of Science and Technology, High Performance Computing Center North (HPC2N).
    Exploring the dynamics of shikimate kinase through molecular mechanics2022In: Biophysica, ISSN 2673-4125, Vol. 2, no 3, p. 194-202Article in journal (Refereed)
    Abstract [en]

    Shikimate kinase (SK) enzyme is a suitable target for antimicrobial drugs as it is present in pathogenic microorganisms and absent in mammals. A complete understanding of the functioning of this enzyme can unveil novel methods to inactivate it. To do this, a clear understanding of SK performance is needed. Previously, the chemical step of SK was studied in detail, but a study of longer-term scale simulations is still missing. In the present work, we performed molecular dynamics (MD) simulations in the µs time scale that allowed us to explore further regions of the SK energy landscape than previously. Simulations were conducted on the wild-type (WT) enzyme and the R116A and R116K mutants. We analyzed the dynamics of the enzymes through standard MD tools, and we found that the global motions in the mutants were perturbed. These motions can be linked to the observed undetectable binding affinity of the WT enzyme and the R116A and R116K mutants.

    Download full text (pdf)
    fulltext
  • 8.
    Ojeda-May, Pedro
    Umeå University, Faculty of Science and Technology, High Performance Computing Center North (HPC2N).
    Exploring the mechanism of shikimate kinase through quantum mechanical and molecular mechanical (QM/MM) methods2021In: Biophysica, ISSN 2673-4125, Vol. 1, no 3, p. 334-343Article in journal (Refereed)
    Abstract [en]

    The chemical step of Shikimate Kinase Helicobacter pylori, involving the transfer of a phosphoryl group, has been studied by using quantum mechanical and molecular mechanical (QM/MM) methods. Understanding the mechanism of this chemical step, present in bacteria and other microorganisms but absent in humans, can lead to the development of novel drugs for the treatment of common diseases caused by those pathogenic organisms. Different mechanisms including associative, dissociative, and concerted have been proposed up to now but there is not a consensus on the type of pathway that the reaction follows. Herein, we found that the mechanism has features from the associative and concerted types. An analysis of the free energy landscape of the chemical step reveals that the reaction is a two-step process without a well-defined intermediate state.

    Download full text (pdf)
    fulltext
  • 9.
    Ojeda-May, Pedro
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Computational Life Science Cluster (CLiC).
    Li, Yaozong
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Computational Life Science Cluster (CLiC).
    Ovchinnikov, Victor
    Nam, Kwangho
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Computational Life Science Cluster (CLiC).
    Role of Protein Dynamics in Allosteric Control of the Catalytic Phosphoryl Transfer of Insulin Receptor Kinase2015In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 137, no 39, p. 12454-12457Article in journal (Refereed)
    Abstract [en]

    The catalytic and allosteric mechanisms of insulin receptor kinase (IRK) are investigated by a combination of ab initio and semiempirical quantum mechanical and molecular mechanical (QM/MM) methods and classical molecular dynamics (MD) simulations. The simulations reveal that the catalytic reaction proceeds in two steps, starting with the transfer of a proton from substrate Tyr to the catalytic Asp1132, followed by the phosphoryl transfer from ATP to substrate Tyr. The enhancement of the catalytic rate of IRK upon phosphorylations in the enzyme's activation loop is found to occur mainly via changes to the free energy landscape of the proton transfer step, favoring the proton transfer in the fully phosphorylated enzyme. In contrast, the effects of the phosphorylations on the phosphoryl transfer are smaller. Equilibrium MD simulations show that IRK phosphorylations affect the protein dynamics of the enzyme before the proton transfer to Asp1132 with only a minor effect after the proton transfer. This finding is consistent with the large change in the proton transfer free energy and the smaller change in the free energy barrier of phosphoryl transfer found by QM/MM simulations. Taken together, the present results provide details on how IRK phosphorylation exerts allosteric control of the catalytic activity via modifications of protein dynamics and free energy landscape of catalytic reaction. The results also highlight the importance of protein dynamics in connecting protein allostery and catalysis to control catalytic activity of enzymes.

  • 10.
    Ojeda-May, Pedro
    et al.
    Umeå University, Faculty of Science and Technology, High Performance Computing Center North (HPC2N). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nam, Kwangho
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, Texas 76019-0065, United States.
    Acceleration of Semiempirical QM/MM Methods through Message Passage Interface (MPI), Hybrid MPI/Open Multiprocessing, and Self-Consistent Field Accelerator Implementations2017In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 13, no 8, p. 3525-3536Article in journal (Refereed)
    Abstract [en]

    The strategy and implementation of scalable and efficient semiempirical (SE) QM/MM methods in. CHARMM are described. The serial version of the code was first profiled to identify routines that required parallelization. Afterward, the code was parallelized and accelerated with three approaches. The first approach was the parallelization of the entire QM/MM routines, including the Fock matrix diagonalization routines, using the CHARMM message passage interface (MPI) machinery. In the second approach, two different self-consistent.field (SCF) energy convergence accelerators were implemented using density and Pock matrices as targets for their extrapolations in the SCF procedure. In the third approach, the entire QM/MM and MM energy routines were accelerated by implementing the hybrid MPI/open multiprocessing (OpenMP) model in which both the task- and loop-leveL parallelitation strategies were adopted to balance loads between different OpenMP threads. The present implementation was tested on two solvated enzyme systems (including <100 QM atoms) and an S(N)2 symmetric reaction in water. The-MPI version exceeded existing SE QM methods in CHARMM which include the SCC-DFTB and SQUANTUM methods by at least 4-fold. The use of SCF convergence accelerators further accelerated,the code by similar to 12-35% depending on the size of the QM region and the number of CPU cores used. Although the MPI version displayed good scalability, the performance was diminished for large numbers of MPI processes due to the overhead associated with MPI communications between nodes. This issue was partially overcome by the hybrid MPI/OpenMP approach which displayed a better scalability for a larger number of CPU cores (up to 64 CPUs in the tested systems).

  • 11.
    Ojeda-May, Pedro
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Science and Technology, High Performance Computing Center North (HPC2N).
    Ul Mushtaq, Ameeq
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Rogne, Per
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Verma, Apoorv
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ovchinnikov, Victor
    Grundström, Christin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Dulko-Smith, Beata
    Sauer, Uwe H.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wolf-Watz, Magnus
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nam, Kwangho
    Dynamic Connection between Enzymatic Catalysis and Collective Protein Motions2021In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 60, no 28, p. 2246-2258Article in journal (Refereed)
    Abstract [en]

    Enzymes employ a wide range of protein motions to achieve efficient catalysis of chemical reactions. While the role of collective protein motions in substrate binding, product release, and regulation of enzymatic activity is generally understood, their roles in catalytic steps per se remain uncertain. Here, molecular dynamics simulations, enzyme kinetics, X-ray crystallography, and nuclear magnetic resonance spectroscopy are combined to elucidate the catalytic mechanism of adenylate kinase and to delineate the roles of catalytic residues in catalysis and the conformational change in the enzyme. This study reveals that the motions in the active site, which occur on a time scale of picoseconds to nanoseconds, link the catalytic reaction to the slow conformational dynamics of the enzyme by modulating the free energy landscapes of subdomain motions. In particular, substantial conformational rearrangement occurs in the active site following the catalytic reaction. This rearrangement not only affects the reaction barrier but also promotes a more open conformation of the enzyme after the reaction, which then results in an accelerated opening of the enzyme compared to that of the reactant state. The results illustrate a linkage between enzymatic catalysis and collective protein motions, whereby the disparate time scales between the two processes are bridged by a cascade of intermediate-scale motion of catalytic residues modulating the free energy landscapes of the catalytic and conformational change processes.

  • 12.
    Ojeda-May, Pedro
    et al.
    Umeå University, Faculty of Science and Technology, High Performance Computing Center North (HPC2N).
    Vergara, Alexander
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Physics.
    Effects of colored noise in the dynamic motions and conformational exploration of enzymes2024In: Foundations, E-ISSN 2673-9321, Vol. 4, no 3, p. 324-335Article in journal (Refereed)
    Abstract [en]

    The intracellular environment displays complex dynamics influenced by factors such as molecular crowding and the low Reynolds number of the cytoplasm. Enzymes exhibiting active matter properties further heighten this complexity which can lead to memory effects. Molecular simulations often neglect these factors, treating the environment as a “thermal bath” using the Langevin equation (LE) with white noise. One way to consider these factors is by using colored noise instead within the generalized Langevin equation (GLE) framework, which allows for the incorporation of memory effects that have been observed in experimental data. We investigated the structural and dynamic differences in Shikimate kinase (SK) using LE and GLE simulations. Our results suggest that GLE simulations, which reveal significant changes, could be utilized for assessing conformational motions’ impact on catalytic reactions.

    Download full text (pdf)
    fulltext
  • 13.
    Zhou, Y.
    et al.
    Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States.
    Ojeda-May, Pedro
    Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States.
    Nagaraju, M.
    Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States.
    Pu, J.
    Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States.
    Toward determining ATPase mechanism in ABC transporters2016In: Computational approaches for studying enzyme mechanism part A / [ed] Gregory A. Voth, Elsevier, 2016, Vol. 577, p. 185-212Chapter in book (Refereed)
    Abstract [en]

    Adenosine triphosphate (ATP)-binding cassette (ABC) transporters are ubiquitous ATP-dependent membrane proteins involved in translocations of a wide variety of substrates across cellular membranes. To understand the chemomechanical coupling mechanism as well as functional asymmetry in these systems, a quantitative description of how ABC transporters hydrolyze ATP is needed. Complementary to experimental approaches, computer simulations based on combined quantum mechanical and molecular mechanical (QM/MM) potentials have provided new insights into the catalytic mechanism in ABC transporters. Quantitatively reliable determination of the free energy requirement for enzymatic ATP hydrolysis, however, requires substantial statistical sampling on QM/MM potential. A case study shows that brute force sampling of ab initio QM/MM (AI/MM) potential energy surfaces is computationally impractical for enzyme simulations of ABC transporters. On the other hand, existing semiempirical QM/MM (SE/MM) methods, although affordable for free energy sampling, are unreliable for studying ATP hydrolysis. To close this gap, a multiscale QM/MM approach named reaction path–force matching (RP–FM) has been developed. In RP–FM, specific reaction parameters for a selected SE method are optimized against AI reference data along reaction paths by employing the force matching technique. The feasibility of the method is demonstrated for a proton transfer reaction in the gas phase and in solution. The RP–FM method may offer a general tool for simulating complex enzyme systems such as ABC transporters.

  • 14. Zhou, Yan
    et al.
    Ojeda-May, Pedro
    Umeå University, Faculty of Science and Technology, High Performance Computing Center North (HPC2N).
    Nagaraju, Mulpuri
    Kim, Bryant
    Pu, Jingzhi
    Mapping Free Energy Pathways for ATP Hydrolysis in the E. coli ABC Transporter HlyB by the String Method2018In: Molecules, ISSN 1431-5157, E-ISSN 1420-3049, Vol. 23, no 10, p. 1-22, article id 2652Article in journal (Refereed)
    Abstract [en]

    HlyB functions as an adenosine triphosphate (ATP)-binding cassette (ABC) transporter that enables bacteria to secrete toxins at the expense of ATP hydrolysis. Our previous work, based on potential energy profiles from combined quantum mechanical and molecular mechanical (QM/MM) calculations, has suggested that the highly conserved H-loop His residue H662 in the nucleotide binding domain (NBD) of E. coli HlyB may catalyze the hydrolysis of ATP through proton relay. To further test this hypothesis when entropic contributions are taken into account, we obtained QM/MM minimum free energy paths (MFEPs) for the HlyB reaction, making use of the string method in collective variables. The free energy profiles along the MFEPs confirm the direct participation of H662 in catalysis. The MFEP simulations of HlyB also reveal an intimate coupling between the chemical steps and a local protein conformational change involving the signature-loop residue S607, which may serve a catalytic role similar to an Arg-finger motif in many ATPases and GTPases in stabilizing the phosphoryl-transfer transition state.

    Download full text (pdf)
    fulltext
1 - 14 of 14
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf