Åqvist lab

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Research projects

Biological Catalysis

List of Publications

Johansson DGA, Wallin G, Sandberg A, Macao B, Åqvist J and Härd T; Protein Autoproteolysis: Conformational Strain Linked to the Rate of Peptide Cleavage by the pH Dependence of the N -> O Acyl Shift Reaction J. Am. Chem. Soc.131, 9475, (2009

Bjelic, S., Brandsdal, BO., Aqvist, J. Cold Adaptation of Enzyme Reaction Rates Biochemistry47, 10049, (2008)

Thomaeus, A., Carlsson, J., Åqvist, J., Widersten, M. Active Site of Epoxide Hydrolases Revisited: a Non-Canonical Residue in Potato StEH1 Promotes Both Formation and Breakdown of the Alkylenzyme Intermediate. Biochemistry46, 2466, (2007)

Henriksson, L.M., Unge, T., Carlsson, J., Åqvist, J., Mowbray, S.L., Jones, T.A. Structures of Mycobacterium tuberculosis 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase Provide New Insights into Catalysis. J. Biol. Chem.282, 19905, (2007)

Bjelic, S., Åqvist, J. Catalysis and Linear Free Energy Relationships in Aspartic Proteases. Biochemistry45, 7709, (2006)

Bjelic, S., Åqvist, J. Computational Prediction of Structure, Substrate Binding Mode, Mechanism and Rate for a Malaria Protease with a Novel Type of Active Site. Biochemistry43, 14521, (2004)

Membrane Channels and Receptors

G protein coupled receptors (GPCRs) are a superfamily of membrane receptors of extraordinarily pharmacological interest, being the main target of more than 30% of the marketed drugs. With the number of experimental GPCR structures growing fast, Computational Biology is playing a major role in the further elucidation of new structures, providing a better understanding receptor dynamics and importantly contributing to the design of new ligands. Our activities in this area is organized around the following topics:
• GPCR structure prediction: Our pipeline for the modeling and simulation of GPCRs is centralized at the GPCR-ModSim web server.
• Characterization of the Neuropeptide-Y receptor family and related peptide-binding GPCRs: in collaboration with the Dan Larhammar’s group at the Neurosciences department.
• Discovery and design of GPCR ligands: We currently focus on the design of potent and selective antagonists for the adenosine receptors, in collaboration with the Combinatorial Chemistry group of Eddy Sotelo, USC.
• Molecular dynamics and free energy calculations can reveal insights into structure-function and structure-activity relationships: we are working on the characterization of the conformational equilibrium of GPCRs, the mechanism of allosteric control and a computational prediction of the effects of single-point mutations on receptor stability and ligand binding.

List of Publications

Boukharta, L.; Gutiérrez-de-Terán, H.; Åqvist, J. Computational prediction of alanine scanning and ligand binding energetics in G-protein coupled receptors. PlOS Comp. Biol. (2014) 10:exxx (in press).

Gutiérrez-de-Terán, H. The roles of computational chemistry in the ligand design of G protein-coupled receptors: how far have we come and what should we expect? Fut. Med. Chem. (2014) 6:251-54.

Gutiérrez-de-Terán, H. ; Massinkc, A.; Rodríguez, D.; Liu, W.; Han, G.W.; Joseph, J. S.; Katritch, I.; Heitman, L. H.; Xia, L.; IJzerman, A.; Cherezov, V.; Katritch, V.; Stevens, R. C. The role of a sodium ion binding site in the allosteric modulation of the A2A adenosine G protein-coupled receptor. Structure (2013) 21:2175-85.

Xu,B.; Fällmar,H.; Boukharta,L.; Pruner,J.; Lundell,I.;Mohell,N.; Gutiérrez-de-Terán,H.; Åqvist, J.; Larhammar, D. Mutagenesis and computational modeling of the human G protein-coupled receptor Y2 for neuropeptide Y and peptide YY Biochemistry (2013) 52:7987-98.

Crespo, A.; El Maatougui, A.; Biagini, P.; Azuaje, J.; Coelho, A.; Brea, P.; Loza, M.I.; Cadavid, M.I.; García-Mera, X.; Gutiérrez-de-Terán, H. and Sotelo, E. Discov- ery of 3,4-Dihydropyrimidin-2(1H)-ones as a Novel Class of Potent and Selective A2B Adenosine Receptor Antagonists. ACS Med. Chem. Lett. (2013) 4:1031-1036.

Yaziji, V.; Rodríguez, D.; Coelho, A.; García-Mera, X.; Brea, J.; Loza, M.I.; Cadavid, M.I.; Gutiérrez-de-Terán, H.; Sotelo, E.: Selective and Potent Adenosine A3 Receptor Antagonists by Methoxyaryl Substitution on the N(2,6-Diarylpyrimidin- 4-yl)acetamide scaffold. Eur. J. Med. Chem. (2013) 59:235-42.

Gutiérrez-de-Terán, H.*; Bello, X.; Rodríguez, D. (* corresponding author): Characterization of the dynamic events of GPCRs by automated computational simulations. Biochem. Soc Trans (2013), 41:205-212.

Boukharta, L, Keränen, H, Stary-Weinzinger, A, Wallin, G, de Groot, BL, Aqvist, J.; Computer simulations of structure-activity relationships for HERG channel blockers Biochemistry50, 6146, (2011)

Åkerberg, H., Fällmar, H., Sjödin, P., Boukharta, L., Gutiérrez-de-Terán, H., Lundell, I., Mohell, N., Larhammar, D. Mutagenesis of human neuropeptide Y/peptide YY receptor Y2 reveals additional differences to Y1 in interactions with highly conserved ligand positions Regul. Peptides 163, 120, (2010)

Stary, A., Wacker, S. J., Boukharta, L., Zachariae, U., Karimi-Nejad, Y., Åqvist, J., Vriend, G., de Groot, B. L. Toward a Consensus Model of the hERG Potassium Channel ChemMedChem5, 455, (2010)

Johansson, C., Boukharta, L., Eriksson, J., Åqvist, J., Sundström, L. Mutagenesis and Homology Modeling of the Tn21 Integron Integrase IntI1 Biochemistry48, 1743, (2009)

Andér, M., Luzhkov, V.B., Åqvist, J. Ligand binding to the voltage gated Kv1.5 potassium channel in the open state - docking and computer simulations of a homology model. Biophys. J.94, 820, (2008)

Luzhkov, V., Almlöf, M., Nervall, M., Åqvist, J. Computational Study of Binding Affinity and Selectivity of the Bacterial Ammonium Transporter AmtB. Biochemistry45, 10807, (2006)

Österberg, F., Åqvist, J. Exploring Blocker Binding to a Homology Model of the Open hERG K+ Channel using Docking and Molecular Dynamics Methods. FEBS Lett.579, 2939, (2005)

Luzhkov, V.B., Åqvist, J. Ions and Blockers in Potassium Channels: Insights from Free Energy Simulations. Biochim. Biophys. Acta1747, 109, (2005)

Luzhkov, V.B., Nilsson, J., Århem, P., Åqvist, J. Computational Modeling of the Open-State Kv1.5 Ion Channel Block by Bupivacaine. Biochim. Biophys. Acta1652, 35, (2003)

Luzhkov, V.B., Österberg, F., Åqvist J. Structure-Activity Relationship for Extracellular Block of K+ Channels by Tetraalkylammonium Ions. FEBS Lett.554, 159, (2003)

Methods Development

List of Publications

Keränen, Gutiérrez-de-Terán H, Åqvist J. (2014) PLoS One. 9, 1-12. "Structural and Energetic Effects of A2A Adenosine Receptor Mutations on Agonist and Antagonist Binding". Open Access.

Shamsudin Khan Y, Gutiérrez-de-Terán H, Boukharta L, Åqvist J. (2014). J Chem Inf Model. 54, 1488-1499. "Toward an Optimal Docking and Free Energy Calculation Scheme in Ligand Design with Application to COX‐1 Inhibitors"

Boukharta L, Gutiérrez-de-Terán H, Åqvist J. (2014) PLoS Comput Biol. 10, 1-11. "Computational prediction of alanine scanning and ligand binding energetics in G-protein coupled receptors". Open Access.

Almlöf, M., Åqvist, J., Smalås, A.O., Brandsdal, B.O. Probing the Effect of Point Mutations at Protein-Protein Interfaces with Free Energy Calculations. Biophys. J.90, 433, (2006)

Carlsson, J., Andér, M., Nervall, M., Åqvist, J. Continuum Solvation Models in the Linear Interaction Energy Method. J. Phys. Chem. B110, 12034, (2006)

Carlsson, J., Åqvist, J. Calculations of Solute and Solvent Entropies from Molecular Dynamics Simulations. Phys. Chem. Chem. Phys.8, 5385, (2006)

Carlsson, J., Åqvist, J. Absolute and Relative Entropies from Computer Simulation with Applications to Ligand Binding. J. Phys. Chem. B109, 6448, (2005)

Almlöf, M., Brandsdal B.O., Åqvist, J. Binding Affinity Prediction with Different Force Fields: Evaluation of the Linear Interaction Energy Method. J. Comput. Chem.25, 1242, (2004)

Åqvist, J., Wennerström, P., Nervall, M., Bjelic, S., Brandsdal, B.O. Molecular Dynamics Simulations of Water and Biomolecules with a Monte Carlo Constant Pressure Algorithm. Chem. Phys. Lett.384, 288, (2004)

Structure-Based Ligand Design

List of Publications

Aqvist, J., Lind, C., Sund, J., Wallin, G. (2012). Bridging the gap between ribosome structure and biochemistry by mechanistic computations. Current opinion in structural biology, 22(6): 815-823

Wallin G and Åqvist J; The transition state for peptide bond formation reveals the ribosome as a water trap Proc Natl Acad Sci U S A107, 1888, (2010)

Sund, J., Andér, M., and Åqvist, J. Principles of stop-codon reading on the ribosome Nature465, 947, (2010)

Andér, M, Åqvist, J Does Glutamine Methylation Affect the Intrinsic Conformation of the Universally Conserved GGQ Motif in Ribosomal Release Factors? Biochemistry48, 3483, (2009)

Almlöf, M., Andér, M., Åqvist, J. Energetics of Codon-Anticodon Recognition on the Small Ribosomal Subunit. Biochemistry46, 200, (2007)

Trobro, S., Åqvist, J. A model for how ribosomal release factors induce peptidyl-tRNA cleavage in termination of protein synthesis Mol. Cell27, 758, (2007)

Trobro, S., Åqvist, J. Analysis of Predictions for the Catalytic Mechanism of Ribosomal Peptidyl transfer. Biochemistry45, 7049, (2006)

Trobro, S., Åqvist, J. Mechanism of Peptide Bond Synthesis on the Ribosome. Proc. Natl. Acad. Sci. U.S.A.102, 12395, (2005)

Ribosome Computations

With the use of Molecular Dynamics simulations coupled to the Linear Interaction Energy (LIE) Method properties of ligand binding can be deduced. This method has been successfully used in a variety of biological systems, including COX-1, HIV-1 reverse transcriptase and Plasmepsin Plm II and IV.

List of Publications

Sund J, Lind C, Åqvist J., (2014) J Phys Chem B. "Binding Site Preorganization and Ligand Discrimination in the Purine Riboswitch".

Shamsudin Khan Y, Gutiérrez-de-Terán H, Boukharta L, Åqvist J. (2014). J Chem Inf Model. 54, 1488-1499. "Toward an Optimal Docking and Free Energy Calculation Scheme in Ligand Design with Application to COX‐1 Inhibitors"

Boukharta L, Gutiérrez-de-Terán H, Åqvist J. (2014) PLoS Comput Biol. 10, 1-11. "Computational prediction of alanine scanning and ligand binding energetics in G-protein coupled receptors". Open Access.

Wallin G, Nervall M, Carlsson J and Åqvist J; Charges for Large Scale Binding Free Energy Calculations with the Linear Interaction Energy Method J. Chem. Theory Comput.5, 380, (2009)

Nervall, M., Hanspers, P., Carlsson, J., Boukharta, L., Åqvist, J. Predicting binding modes from free energy calculations. J. Med. Chem.51, 2657, (2008)

Carlsson, J., Boukharta, L., Aqvist, J. Combining docking, molecular dynamics and the linear interaction energy method to predict binding modes and affinities for non-nucleoside inhibitors to HIV-1 reverse transcriptase. J. Med. Chem.51, 2648, (2008)

Ersmark, K., Nervall, M., Guiterrez de Teran, H., Hamelink, E., Janka, L.K., Clemente, J.C., Dunn, B.M., Gogoll, A., Samuelsson, B., Åqvist, J., Hallberg, A. Macrocyclic Inhibitors of the Malarial Aspartic Proteases Plasmepsin Plm II and IV. Bioorg, Med. Chem.14, 2197, (2006)

Guiterrez de Teran, H., Nervall, M., Ersmark, K., Liu, P., Janka, L.K., Dunn, B., Hallberg, A., Åqvist, J. Inhibitor Binding to the Plasmepsin IV Aspartic Protease from Plasmodium falciparum. Biochemistry45, 10529, (2006)

Guiterrez-de-Teran, H., Nervall, M., Dunn, B.M., Clemente, J.C., Åqvist, J. Computational Analysis of Plasmepsin IV Bound to an Allophenylnorstatine Inhibitor. FEBS Lett.580, 5910, (2006)

Lovmar, M., Nilsson, K., Vimberg, V., Tenson, T., Nervall, M., Ehrenberg, M. The Molecular Mechanism of Peptide-Mediated Erythromycin Resistance. J. Biol. Chem.281, 6742, (2006)

Ersmark, K., Nervall, M., Hamelink, E., Janka, L.K., Clemente, J.C., Dunn, B.M., Blackman, M.J., Samuelsson, B., Åqvist, J., Hallberg, A. Synthesis of Malarial Plasmepsin Inhibitors and Prediction of Binding Modes by Molecular Dynamics Simulations. J. Med. Chem.48, 6090, (2005)

Ersmark, K., Bjelic, S., Feierberg, I., Hamerlink, E., Hackett, F., Blackman, M.J., Hultén J., Samuelsson, B., Åqvist, J., Hallberg, A. Potent Inhibitors of the P. falciparum Enzymes Plasmepsin I and II Devoid of Cathepsin D Inhibitory Activity. J. Med. Chem.47, 110, (2004)

Ersmark, K., Feierberg, I., Bjelic, S., Hultén J., Samuelsson, B., Åqvist, J., Hallberg, A. C2-Symmetric Inhibitors of Plasmodium falciparum Plasmepsin II: Synthesis and Theoretical Predictions. Bioorg. Med. Chem.11, 3723, (2003)