8 research outputs found
Haptic Rendering Based on RBF Approximation from Dynamically Updated Data
In this paper, an extension of our previous research focused on haptic rendering based on interpolation from precomputed data is presented. The technique employs the radial-basis function (RBF) interpolation to achieve the accuracy of the force response approximation, however, it assumes that the data used by the interpolation method are generated on-the-fly during the haptic interaction. The issue caused by updating the RBF coefficients during the interaction is analyzed and a force-response smoothing strategy is proposed
CaverDock: Software tool for fast screening of un/binding of ligands in protein engineering
Protein tunnels, channels and gates are important for enzymatic catalysis and also represent attractive targets for rational protein design and drug design [1]. Drug molecules blocking the access of natural substrate or release of products are very efficient modulators of biological activity. Here we demonstrate the application of newly in-house developed software tool CaverDock [2,3] for the analysis of the transport of ligands through tunnels in biomolecular targets. Caverdock is a new addition to the Caver Suite [4-6]. We performed virtual screening of large databases of drugs against two pharmacologically relevant targets. We have used FDA-approved drugs for both targets. Oncological drugs (133 molecules), taken from the NIH website, and anti-inflammatory (56 molecules), taken from the Drugbank website, as the libraries of ligands for the two molecular targets: (i) cytochrome P450 17A1 and (ii) leukotriene A4 hydrolase/aminopeptidase. Moreover, we will also show the unbinding of the 2,3-dichloropropan-1-ol product from a buried active site of an haloalkane dehalogenase and its variant. With this study we identified hot-spots that may be used for directed evolution or site-directed mutagenesis to create new variants for faster 2,3-dichloropropan-1-ol release [7]. Finally, we will show the difference on ligand transportation when a protein is in an open and closed conformations [8]. We will show how CaverDock tackles the problem of protein flexibility.
1. Marques, S.M., et al., 2017: Enzyme Tunnels and Gates as Relevant Targets in Drug Design. Medicinal Research Reviews 37: 1095-1139.
2. Vavra, O., et al., 2019: CaverDock 1.0: A New Tool for Analysis of Ligand Binding and Unbinding Based on Molecular Docking. Bioinformatics (under review).
3. Filipovic, J., et al, 2019: A Novel Method for Analysis of Ligand Binding and Unbinding Based on Molecular Docking. Transactions on Computational Biology and Bioinformatics (under review)
4. Chovancova, E., et al., 2012: CAVER 3.0: A Tool for Analysis of Transport Pathways in Dynamic Protein Structures. PLOS Computational Biology 8: e1002708.
5. Jurcik, A., et al., 2018: CAVER Analyst 2.0: Analysis and Visualization of Channels and Tunnels in Protein Structures and Molecular Dynamics Trajectories. Bioinformatics 34: 3586-3588.
6. Stourac, J., et al., 2019: Caver Web 1.0: Identification of Tunnels and Channels in Proteins and Analysis of Ligand Transport. Nucleic Acids Research (under review).
7. Marques, S.M., et al., 2019: Computational Study of Protein-Ligand Unbinding for Enzyme Engineering. Frontiers in Chemistry 6: 650.
8. Kokkonen, P., et al., 2018: Molecular Gating of an Engineered Enzyme Captured in Real Time. Journal of the American Chemical Society 140: 17999â18008
Strategies and software tools for engineering protein tunnels and dynamical gates
Improvements in the catalytic activity, substrate specificity or enantioselectivity of enzymes are traditionally achieved by modification of enzymesâ active sites. We have recently proposed that the enzyme engineering endeavors should target both the active sites and the access tunnels/channels [1,2]. Using the model enzymes haloalkane dehalogenases, we have demonstrated that engineering of access tunnels provides enzymes with significantly improved catalytic properties [3] and stability [4]. User-friendly software tools Caver [5], Caver Analyst [6], CaverDock [7] and Caver Web [8], have been developed for the computational design of protein tunnels/channels; FireProt [9] and HotSpot Wizard [10] for automated design of stabilizing mutations and smart libraries. Using these tools we were able to introduce a new tunnel to a protein structure and tweak its conformational dynamics. This engineering strategy has led to improved catalytic efficiency [2], enhanced promiscuity or even a functional switch (unpublished). Our concepts and software tools are widely applicable to various enzymes with known structures and buried active sites.
1. Damborsky, J., et al., 2009: Computational Tools for Designing and Engineering Biocatalysts. Current Opinion in Chemical Biology 13: 26-34.
2. Prokop, Z., et al., 2012: Engineering of Protein Tunnels: Keyhole-lock-key Model for Catalysis by the Enzymes with Buried Active Sites. Protein Engineering Handbook, Wiley-VCH, Weinheim, pp. 421-464.
3. Brezovsky, J., et al., 2016: Engineering a de Novo Transport Tunnel. ACS Catalysis 6: 7597-7610.
4. Koudelakova, T., et al., 2013: Engineering Enzyme Stability and Resistance to an Organic Cosolvent by Modification of Residues in the Access Tunnel. Angewandte Chemie 52: 1959-1963.
5. Chovancova, E., et al., 2012: CAVER 3.0: A Tool for Analysis of Transport Pathways in Dynamic Protein Structures. PLOS Computational Biology 8: e1002708.
6. Jurcik, A., et al., 2018: CAVER Analyst 2.0: Analysis and Visualization of Channels and Tunnels in Protein Structures and Molecular Dynamics Trajectories. Bioinformatics 34: 3586-3588.
7. Vavra, O., et al., 2019: CaverDock 1.0: A New Tool for Analysis of Ligand Binding and Unbinding Based on Molecular Docking. Bioinformatics (under review).
8. Stourac, J., et al. 2019: Caver Web 1.0: Identification of Tunnels and Channels in Proteins and Analysis of Ligand Transport. Nucleic Acids Research (under review).
9. Musil, M., et al., 2017: FireProt: Web Server for Automated Design of Thermostable Proteins. Nucleic Acids Research 45: W393-W399.
10. Sumbalova, L. et al., 2018: HotSpot Wizard 3.0: Automated Design of Site-Specific Mutations and Smart Libraries in Protein Engineering. Nucleic Acids Research 46: W356-W362
CAVERDOCK: A new tool for analysis of ligand binding and unbinding based on molecular docking
Understanding the protein-ligand interactions is crucial for engineering improved catalysts. The interaction of a protein and a ligand molecule often takes place in enzymes active site. Such functional sites may be buried inside the protein core, and therefore a transport of a ligand from outside environment to the protein inside needs to be understood. Here we present the CaverDock [1], implementing a novel method for analysis of these important transport processes. Our method is based on a modified molecular docking algorithm. It iteratively places the ligand along the tunnel in such a way that the ligand movement is contiguous and its energy is minimized. The output of the calculation is ligand trajectory and energy profile of transport process. CaverDock uses a modified version of the program AutoDock Vina [2] for molecular docking and implements a parallel heuristic algorithm to search the space of possible trajectories. Our method lies in between of geometrical approaches and molecular dynamics simulations. Contrary to geometrical methods, it provides an evaluation of chemical forces. However, it is not as computationally demanding as the methods based on molecular dynamics. The typical input of CaverDock requires setup for molecular docking and tunnel geometry obtained from Caver [3]. Typical computational time is in dozens of minutes at a single node, allowing virtual screening of a large pool of molecules. We demonstrate CaverDock usability by comparison of a ligand trajectory in different tunnels of wild type and engineered proteins; and computation of energetic profiles for a large set of substrates and inhibitors. CaverDock is available from the web site http://www.caver.cz.
1. Vavra, O., Filipovic, J., Plhak, J., Bednar, D., Marques, S., Brezovsky, J., Matyska, L., Damborsky, J., CAVERDOCK: A New Tool for Analysis of Ligand Binding and Unbinding Based on Molecular Docking. PLOS Computational Biology (submitted).
2. Trott, O., Olson, A.J., AutoDock Vina: Improving the Speed and Accuracy of Docking with a New scoring function, efficient optimization and multithreading, Journal of Computational Chemistry 31: 455-461, 2010.
3. Chovancova, E., Pavelka, A., Benes, P., Strnad, O., Brezovsky, J., Kozlikova, B., Gora, A., Sustr, V., Klvana, M., Medek, P., Biedermannova, L., Sochor, J., Damborsky, J., 2012: CAVER 3.0: A Tool for Analysis of Transport Pathways in Dynamic Protein Structures. PLOS Computational Biology 8: e1002708
Advances in Xmipp for cryo-electron microscopy: from Xmipp to Scipion
Xmipp is an open-source software package consisting of multiple programs for processing data originating from electron microscopy and electron tomography, designed and managed by the Biocomputing Unit of the Spanish National Center for Biotechnology, although with contributions from many other developers over the world. During its 25 years of existence, Xmipp underwent multiple changes and updates. While there were many publications related to new programs and functionality added to Xmipp, there is no single publication on the Xmipp as a package since 2013. In this article, we give an overview of the changes and new work since 2013, describe technologies and techniques used during the development, and take a peek at the future of the package
Screening of World Approved Drugs against Highly Dynamical Spike Glycoprotein SARS-CoV-2 using CaverDock and Machine Learning
The
new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes pathological
pulmonary symptoms. Most efforts to develop vaccines and drugs against this
virus target the spike glycoprotein, particularly its S1 subunit, which is
recognised by angiotensin-converting enzyme 2. Here we use the in-house developed tool CaverDock to
perform virtual screening against spike glycoprotein using a cryogenic electron
microscopy structure (PDB-ID: 6VXX) and the representative structures of five
most populated clusters from a previously published molecular dynamics
simulations. The dataset of ligands was obtained from the ZINC database and
consists of drugs approved for clinical use worldwide. Trajectories for the passage
of individual drugs through the tunnel of the spike glycoprotein homotrimer,
their binding energies within the tunnel, and the duration of their contacts
with the trimerâs three subunits were computed for the full dataset.
Multivariate statistical methods were then used to establish structure-activity
relationships and select top candidate molecules. This new protocol for rapid screening
of globally approved drugs (4359 ligands) in a multi-state protein structure (6
states) required a total of 26,148 calculations and showed high robustness. The
protocol is universal and can be applied to any target protein with an experimental
tertiary structure containing protein tunnels or channels. The protocol will be
implemented in the next version of CaverWeb (https://loschmidt.chemi.muni.cz/caverweb/)
to make it accessible to the wider scientific communit