scholarly journals Molecular dynamics simulations of galectin-1-oligosaccharide complexes reveal the molecular basis for ligand diversity

2003 ◽  
Vol 53 (2) ◽  
pp. 229-240 ◽  
Author(s):  
Michael G. Ford ◽  
Thomas Weimar ◽  
Thies Köhli ◽  
Robert J. Woods
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Molecular Basis ◽  
Dynamics Simulations

Molecular Basis of Iterative C–H Oxidation by TamI, a Multifunctional P450 Monooxygenase from the Tirandamycin Biosynthetic Pathway

2020 ◽  
Author(s):  
Sean A. Newmister ◽  
Kinshuk Raj Srivastava ◽  
Rosa V. Espinoza ◽  
Kersti Caddell Haatveit ◽  
Yogan Khatri ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Molecular Basis ◽  
Hydrophobic Interactions ◽  
Cytochromes P450 ◽  
Targeted Mutagenesis ◽  
P450 Monooxygenase ◽  
Bond Functionalization ◽  
Dynamics Simulations

Biocatalysis offers an expanding and powerful strategy to construct and diversify complex molecules by C-H bond functionalization. Due to their high selectivity, enzymes have become an essential tool for C-H bond functionalization and offer complementary reactivity to small-molecule catalysts. Hemoproteins, particularly cytochromes P450, have proven effective for selective oxidation of unactivated C-H bonds. Previously, we reported the in vitro characterization of an oxidative tailoring cascade in which TamI, a multifunctional P450 functions co-dependently with the TamL flavoprotein to catalyze regio- and stereoselective hydroxylations and epoxidation to yield tirandamycin A and tirandamycin B. TamI follows a defined order including 1) C10 hydroxylation, 2) C11/C12 epoxidation, and 3) C18 hydroxylation. Here we present a structural, biochemical, and computational investigation of TamI to understand the molecular basis of its substrate binding, diverse reactivity, and specific reaction sequence. The crystal structure of TamI in complex with tirandamycin C together with molecular dynamics simulations and targeted mutagenesis suggest that hydrophobic interactions with the polyene chain of its natural substrate are critical for molecular recognition. QM/MM calculations and molecular dynamics simulations of TamI with variant substrates provided detailed information on the molecular basis of sequential reactivity, and pattern of regio- and stereo-selectivity in catalyzing the three-step oxidative cascade.<br>

scholarly journals Molecular Basis of Bcl-XL-p53 Interaction: Insights from Molecular Dynamics Simulations

PLoS ONE ◽  
2011 ◽  
Vol 6 (10) ◽  
pp. e26014 ◽  
Author(s):  
Nagakumar Bharatham ◽  
Seung-Wook Chi ◽  
Ho Sup Yoon
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Molecular Basis ◽  
Dynamics Simulations

Molecular Basis of Iterative C–H Oxidation by TamI, a Multifunctional P450 Monooxygenase from the Tirandamycin Biosynthetic Pathway

2020 ◽  
Author(s):  
Sean A. Newmister ◽  
Kinshuk Raj Srivastava ◽  
Rosa V. Espinoza ◽  
Kersti Caddell Haatveit ◽  
Yogan Khatri ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Molecular Basis ◽  
Hydrophobic Interactions ◽  
Cytochromes P450 ◽  
Targeted Mutagenesis ◽  
P450 Monooxygenase ◽  
Bond Functionalization ◽  
Dynamics Simulations

Biocatalysis offers an expanding and powerful strategy to construct and diversify complex molecules by C-H bond functionalization. Due to their high selectivity, enzymes have become an essential tool for C-H bond functionalization and offer complementary reactivity to small-molecule catalysts. Hemoproteins, particularly cytochromes P450, have proven effective for selective oxidation of unactivated C-H bonds. Previously, we reported the in vitro characterization of an oxidative tailoring cascade in which TamI, a multifunctional P450 functions co-dependently with the TamL flavoprotein to catalyze regio- and stereoselective hydroxylations and epoxidation to yield tirandamycin A and tirandamycin B. TamI follows a defined order including 1) C10 hydroxylation, 2) C11/C12 epoxidation, and 3) C18 hydroxylation. Here we present a structural, biochemical, and computational investigation of TamI to understand the molecular basis of its substrate binding, diverse reactivity, and specific reaction sequence. The crystal structure of TamI in complex with tirandamycin C together with molecular dynamics simulations and targeted mutagenesis suggest that hydrophobic interactions with the polyene chain of its natural substrate are critical for molecular recognition. QM/MM calculations and molecular dynamics simulations of TamI with variant substrates provided detailed information on the molecular basis of sequential reactivity, and pattern of regio- and stereo-selectivity in catalyzing the three-step oxidative cascade.<br>

scholarly journals Molecular basis of HHQ biosynthesis: molecular dynamics simulations, enzyme kinetic and surface plasmon resonance studies

2013 ◽  
Vol 6 (1) ◽  
pp. 10 ◽  
Author(s):  
Anke Steinbach ◽  
Christine K Maurer ◽  
Elisabeth Weidel ◽  
Claudia Henn ◽  
Christian Brengel ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Surface Plasmon Resonance ◽  
Molecular Dynamics Simulations ◽  
Surface Plasmon ◽  
Plasmon Resonance ◽  
Molecular Basis ◽  
Enzyme Kinetic ◽  
Dynamics Simulations

scholarly journals Molecular basis explanation for imatinib resistance of BCR-ABL due to T315I and P-loop mutations from molecular dynamics simulations

Cancer ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 1744-1753 ◽  
Author(s):  
Tai-Sung Lee ◽  
Steven J. Potts ◽  
Hagop Kantarjian ◽  
Jorge Cortes ◽  
Francis Giles ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Molecular Basis ◽  
Imatinib Resistance ◽  
Dynamics Simulations

scholarly journals Molecular Basis for Spirocycle Formation in the Paraherquamide Biosynthetic Pathway

2019 ◽  
Author(s):  
Amy E. Fraley ◽  
Kersti Caddell Haatveit ◽  
Ying Ye ◽  
Samantha P. Kelly ◽  
Sean A. Newmister ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Natural Products ◽  
Molecular Dynamics Simulations ◽  
Molecular Basis ◽  
Biosynthetic Pathway ◽  
Three Dimensional ◽  
Enzymatic Reactions ◽  
Computational Studies ◽  
Penicillium Simplicissimum ◽  
Dynamics Simulations

<div> <div> <div> <p>The paraherquamides are potent anthelmintic natural products with complex heptacyclic scaffolds. One key feature of these molecules is the spiro-oxindole moiety that lends a strained three-dimensional architecture to these structures. The flavin monooxygenase PhqK was found to catalyze spirocycle formation through two parallel pathways in the biosynthesis of paraherquamides A and G. Two new paraherquamides (K and L) were isolated from a ΔphqK strain of Penicillium simplicissimum, and subsequent enzymatic reactions with these compounds generated two additional metabolites paraherquamides M and N. Crystal structures of PhqK in complex with various substrates provided a foundation for mechanistic analyses and computational studies. While it is evident that PhqK can react with various substrates, reaction kinetics and molecular dynamics simulations indicated that the dioxepin-containing paraherquamide L was the favored substrate. Through this effort, we have elucidated a key step in the biosynthesis of the paraherquamides, and provided a rationale for the selective spirocyclization of these powerful anthelmintic agents. </p></div></div><div><div> </div> </div> </div>

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