ORCID Profile
0000-0003-2714-8200
Current Organisation
Open Molecular Software Foundation
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Publisher: Wiley
Date: 2009
DOI: 10.1002/JCC.21389
Abstract: We present an ONIOM(G3:MM) method as an ex le of a technique capable of producing chemical accuracy in the quantum mechanical (QM) treatment with a molecular mechanical description context. By applying the method to small model systems, in which we are also able to calculate the pure QM G3-type results, it is possible to establish the reliability of the method as it applies to evaluating reaction mechanisms. By choosing small model systems that are relevant to the substrate mechanism of pyruvate formate-lyase, we are also able to discuss the inhibitory effect of oxamate and the relevance of an alternative H-abstraction mechanism in that context.
Publisher: American Chemical Society (ACS)
Date: 17-09-2019
Abstract: Given the need for modern researchers to produce open, reproducible scientific output, the lack of standards and best practices for sharing data and workflows used to produce and analyze molecular dynamics (MD) simulations has become an important issue in the field. There are now multiple well-established packages to perform molecular dynamics simulations, often highly tuned for exploiting specific classes of hardware, each with strong communities surrounding them, but with very limited interoperability/transferability options. Thus, the choice of the software package often dictates the workflow for both simulation production and analysis. The level of detail in documenting the workflows and analysis code varies greatly in published work, hindering reproducibility of the reported results and the ability for other researchers to build on these studies. An increasing number of researchers are motivated to make their data available, but many challenges remain in order to effectively share and reuse simulation data. To discuss these and other issues related to best practices in the field in general, we organized a workshop in November 2018 ( bioexcel.eu/events/workshop-on-sharing-data-from-molecular-simulations/ ). Here, we present a brief overview of this workshop and topics discussed. We hope this effort will spark further conversation in the MD community to pave the way toward more open, interoperable, and reproducible outputs coming from research studies using MD simulations.
Publisher: Wiley
Date: 15-11-2008
DOI: 10.1002/JCC.20984
Abstract: High level ab initio and density functional calculations have been employed to determine the most appropriate manner in which to truncate an arginine-bound carboxylate motif, using the substrate mechanism of Pyruvate Formate-Lyase as a case study. The results show that, both qualitatively and quantitatively, a neutral carboxylic acid provides a more realistic approximation to the salt bridge arrangement than does a bare anionic carboxylate substituent.
Publisher: Figshare
Date: 2017
Publisher: Wiley
Date: 17-07-2016
DOI: 10.1002/PRO.2975
Publisher: American Chemical Society (ACS)
Date: 09-02-2012
DOI: 10.1021/CT2005648
Abstract: The active sites of the (6-4) photolyases contain two conserved histidine residues, which, in the Drosophila melanogaster enzyme, correspond to His365 and His369. While there are nine combinations in which the three possible protonation states of the two histidines (with protons on Nδ (HID), Nε (HIE), or both Nδ and Nε (HIP)) can be paired, there is presently no consensus as to which of these states is present, let alone mechanistically relevant. EPR hyperfine couplings for selected protons of the FADH(•) radical have previously been used to address this issue. Our QM/MM calculations show, however, that the experimental couplings are equally well reproduced by each of the nine combinations. Since the EPR results seemingly cannot be used to unequivocally assign the protonation states, the pKa values of the two histidines were calculated using the popular PROPKA, H++, and APBS approaches, in various environments and for several lesions. These techniques consistently indicate that, at pH = 7, both His365 and His369 should be neutral, although His369 is found to be more prone to becoming protonated. In a comparative approach, a series of molecular dynamics simulations was performed with all nine combinations, employing various reference crystal structures and different oxidation states of the FAD cofactor. The overall result of this approach is in agreement with our pKa results. Consequently, although the introduction of the reduced cofactor results in an increased stability for selected protonated states, particularly the His365═HID and His369═HIP combination, the neutral combination His365═HID and His365═HIE stands out as the most relevant state for the activity of the enzyme.
Publisher: Springer Science and Business Media LLC
Date: 27-12-2009
DOI: 10.1038/NI.1836
Publisher: American Chemical Society (ACS)
Date: 03-10-2019
Abstract: Pyruvate formate-lyase (PFL) is a glycyl radical enzyme that converts pyruvate and coenzyme A (CoA) into formate and acetyl-CoA in two half-reactions. Recently, we showed that the acetylation of the PFL active site in the first half-reaction induces subtle conformational changes, leading to the opening of a potential channel for CoA entry. Entry of CoA into the active site is crucial for the second half-reaction, involving the acetyl transfer to CoA, and the completion of the catalytic cycle. Using steered molecular dynamics (SMD) simulations, performed on acetylated and nonacetylated monomeric PFL model systems, we first of all investigate the possible entry/exit pathways of CoA with respect to the active site through the previously identified channel. We then perform umbrella s ling simulations on multiple snapshots from SMD trajectories as well as unrestrained molecular dynamics simulations starting from the final structures obtained from entry SMD, with a view to identifying possible bound states of CoA in the near vicinity of the active site. Detailed study of the unrestrained dissociation processes reveals the presence of stable and reactive bound states of CoA close to the active site, one of which is in an ideal position for triggering the second half-reaction. Examination of the spatial distributions associated with the reactive bound states allows us to discuss the free energy barriers. Umbrella s ling, performed on snapshots from unrestrained dynamics confirms the above findings. The significance of the results for the catalysis are discussed for both acetylated and nonacetylated systems.
Publisher: Figshare
Date: 2018
Publisher: Proceedings of the National Academy of Sciences
Date: 13-02-2017
Abstract: At this time, multidrug-resistant gram-negative bacteria are estimated to cause approximately 700,000 deaths per year globally, with a prediction that this figure could reach 10 million a year by 2050. Antivirulence therapy, in which virulence mechanisms of a pathogen are chemically inactivated, represents a promising approach to the development of treatment options. The family of lipid A phosphoethanolamine transferases in gram-negative bacteria confers bacterial resistance to innate immune defensins and colistin antibiotics. The development of inhibitors to block lipid A phosphoethanolamine transferase could improve innate immune clearance and extend the usefulness of colistin antibiotics. The solved crystal structure and biophysical studies suggest that the enzyme undergoes large conformational changes to enable binding and catalysis of two very differently sized substrates.
Publisher: Wiley
Date: 09-05-2019
Abstract: Pyruvate formate-lyase (PFL) catalyzes the reversible conversion of pyruvate and coenzyme A (CoA) into formate and acetyl-CoA in two half-reactions. For the second half-reaction to take place, the S-H group of CoA must enter the active site of the enzyme to retrieve a protein-bound acetyl group. However, CoA is bound at the protein surface, whereas the active site is buried in the protein interior, some 20-30 Å away. The PFL system was therefore subjected to a series of extensive molecular dynamics simulations (in the μs range) and a host of advanced analysis procedures. Models representing PFL before and after the first half-reaction were used to examine the possible effect of enzyme acetylation. All simulated structures were found to be relatively stable compared to the initial crystal structure. Although the adenine portion of CoA remained predominantly bound at the protein surface, the binding of the S-H group was significantly more labile. A potential entry channel for CoA, which would allow the S-H group to reach the active site, was identified and characterized. The channel was found to be associated with accentuated fluctuations and a higher probability of being in an open state in acetylated systems. This result suggests that the acetylation of the enzyme assumes a prominent functional role, whereby the formation of the acyl intermediate serves to initiate a subtle signaling cascade that influences the protein dynamics and facilitates the entry of the second substrate.
Publisher: American Chemical Society (ACS)
Date: 18-05-2015
DOI: 10.1021/CI5007382
Abstract: The multidrug transporter P-glycoprotein (P-gp) is central to the development of multidrug resistance in cancer. While residues essential for transport and binding have been identified, the location, composition, and specificity of potential drug binding sites are uncertain. Here molecular dynamics simulations are used to calculate the free energy profile for the binding of morphine and nicardipine to P-gp. We show that morphine and nicardipine primarily interact with key residues implicated in binding and transport from mutational studies, binding at different but overlapping sites within the transmembrane pore. Their permeation pathways were distinct but involved overlapping sets of residues. The results indicate that the binding location and permeation pathways of morphine and nicardipine are not well separated and cannot be considered as unique. This has important implications for our understanding of substrate uptake and transport by P-gp. Our results are independent of the choice of starting structure and consistent with a range of experimental studies.
Publisher: Public Library of Science (PLoS)
Date: 25-01-2018
Publisher: Elsevier BV
Date: 06-2017
Publisher: Figshare
Date: 2018
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.NEUINT.2016.05.005
Abstract: The multidrug transporter P-glycoprotein (P-gp) is expressed in the blood-brain barrier endothelium where it effluxes a range of drug substrates, preventing their accumulation within the brain. P-gp has been studied extensively for 40 years because of its crucial role in the absorption, distribution, metabolism and elimination of a range of pharmaceutical compounds. Despite this, many aspects of the structure-function mechanism of P-gp are unresolved. Here we review the emerging role of molecular dynamics simulation techniques in our understanding of the membrane-embedded conformation of P-gp. We discuss its conformational plasticity in the presence and absence of ATP, and recent efforts to characterize the drug binding sites and uptake pathways.
Publisher: Springer Science and Business Media LLC
Date: 10-2003
Publisher: American Chemical Society (ACS)
Date: 30-11-2016
DOI: 10.1021/ACS.BIOCHEM.6B00683
Abstract: A family of flavin/deazaflavin-dependent oxidoreductases (FDORs) from mycobacteria has been recently characterized and found to play a variety of catalytic roles, including the activation of prodrugs such as the candidate anti-tuberculosis drug pretomanid (PA-824). However, our understanding of the catalytic mechanism used by these enzymes is relatively limited. To address this, we have used a combination of quantum mechanics and molecular dynamics calculations to study the catalytic mechanism of the activation of pretomanid by the deazaflavin-dependent nitroreductase (Ddn) from Mycobacterium tuberculosis. The preferred pathway involves an initial hydride transfer step from the deprotonated cofactor (i.e., F
Location: United States of America
Start Date: 2016
End Date: 2017
Funder: ACT Government
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