scholarly journals Hedgehog proteins create a dynamic cholesterol interface

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246814 ◽  
Author(s):  
Amirhossein Mafi ◽  
Rahul Purohit ◽  
Erika Vielmas ◽  
Alexa R. Lauinger ◽  
Brandon Lam ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Sonic Hedgehog ◽  
Tissue Regeneration ◽  
Molecular Basis ◽  
Signaling Proteins ◽  
Full Structure ◽  
Hedgehog Proteins ◽  
Hh Signaling ◽  
Dynamics Simulations ◽  
Photoaffinity Crosslinking

During formation of the Hedgehog (Hh) signaling proteins, cooperative activities of the Hedgehog INTein (Hint) fold and Sterol Recognition Region (SRR) couple autoproteolysis to cholesterol ligation. The cholesteroylated Hh morphogens play essential roles in embryogenesis, tissue regeneration, and tumorigenesis. Despite the centrality of cholesterol in Hh function, the full structure of the Hint-SRR (“Hog”) domain that attaches cholesterol to the last residue of the active Hh morphogen remains enigmatic. In this work, we combine molecular dynamics simulations, photoaffinity crosslinking, and mutagenesis assays to model cholesterolysis intermediates in the human Sonic Hedgehog (hSHH) protein. Our results provide evidence for a hydrophobic Hint-SRR interface that forms a dynamic, non-covalent cholesterol-Hog complex. Using these models, we suggest a unified mechanism by which Hh proteins can recruit, sequester, and orient cholesterol, and offer a molecular basis for the effects of disease-causing hSHH mutations.

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 Identification of key binding site residues of MCT1 for AR-C155858 reveals the molecular basis of its isoform selectivity

2015 ◽  
Vol 466 (1) ◽  
pp. 177-188 ◽  
Author(s):  
Bethany Nancolas ◽  
Richard B. Sessions ◽  
Andrew P. Halestrap
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Binding Site ◽  
Molecular Basis ◽  
Specific Inhibitor ◽  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Isoform Specificity ◽  
Isoform Selectivity ◽  
Dynamics Simulations

A combination of molecular modelling, site-directed mutagenesis and molecular dynamics simulations define the binding site of MCT1 for AR-C155858, a potent and specific inhibitor. Key amino acids within the binding site differ between MCT1 and MCT4 accounting for isoform specificity.

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 Investigation of the Effects of N-Linked Glycans on the Stability of the Spike Protein in SARS-CoV-2 by Molecular Dynamics Simulations

2022 ◽  
Author(s):  
Emine Deniz Tekin
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Local Stability ◽  
Spike Protein ◽  
Spike Glycoprotein ◽  
Full Structure ◽  
The Stability ◽  
Dynamics Simulations ◽  
Spike Proteins

We perform all-atom molecular dynamics simulations to study the effects of the N-linked glycans on the stability of the spike glycoprotein in SARS-CoV-2. After a 100 ns of simulation on the spike proteins without and with the N-linked glycans, we found that the presence of glycans increases the local stability in their vicinity; even though their effect on the full structure is negligible.

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