+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Regulation and Plasticity of Catalysis in Enzymes: Insights from Analysis of Mechanochemical Coupling in Myosin



Regulation and Plasticity of Catalysis in Enzymes: Insights from Analysis of Mechanochemical Coupling in Myosin



Biochemistry 56(10): 1482-1497



The mechanism of ATP hydrolysis in the myosin motor domain is analyzed using a combination of DFTB3/CHARMM simulations and enhanced sampling techniques. The motor domain is modeled in the pre-powerstroke state, in the post-rigor state, and as a hybrid based on the post-rigor state with a closed nucleotide-binding pocket. The ATP hydrolysis activity is found to depend on the positioning of nearby water molecules, and a network of polar residues facilitates proton transfer and charge redistribution during hydrolysis. Comparison of the observed hydrolysis pathways and the corresponding free energy profiles leads to detailed models for the mechanism of ATP hydrolysis in the pre-powerstroke state and proposes factors that regulate the hydrolysis activity in different conformational states. In the pre-powerstroke state, the scissile Pγ-O bond breaks early in the reaction. Proton transfer from the lytic water to the γ-phosphate through active site residues is an important part of the kinetic bottleneck; several hydrolysis pathways that feature distinct proton transfer routes are found to have similar free energy barriers, suggesting a significant degree of plasticity in the hydrolysis mechanism. Comparison of hydrolysis in the pre-powerstroke state and the closed post-rigor model suggests that optimization of residues beyond the active site for electrostatic stabilization and preorganization is likely important to enzyme design.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 060185549

Download citation: RISBibTeXText

PMID: 28225609

DOI: 10.1021/acs.biochem.7b00016


Related references

Mechanochemical coupling in the myosin motor domain. I. Insights from equilibrium active-site simulations. Plos Computational Biology 3(2): E21, 2007

Mechanochemical coupling in the myosin motor domain. II. Analysis of critical residues. Plos Computational Biology 3(2): E23, 2007

Kinetic analysis of Drosophila muscle myosin isoforms suggests a novel mode of mechanochemical coupling. Journal of Biological Chemistry 278(50): 50293-50300, 2003

A vertebrate myosin-I structure reveals unique insights into myosin mechanochemical tuning. Proceedings of the National Academy of Sciences of the United States of America 111(6): 2116-2121, 2014

Mechanochemical coupling of two substeps in a single myosin V motor. Nature Structural & Molecular Biology 11(9): 877-883, 2004

The significance of myosin light chains in mechanochemical coupling in skeletal muscle. Acta Biochimica Polonica 40(3): 345-351, 1993

Demonstration of mechanochemical coupling in systems containing actin, atp and non-aggregating active myosin derivatives. Journal of Mechanochemistry and Cell Motility 2(4): 295-306, 1974

Human deafness mutation E385D disrupts the mechanochemical coupling and subcellular targeting of myosin-1a. Biophysical Journal 94(2): L5-L7, 2008

A branched kinetic scheme describes the mechanochemical coupling of Myosin Va processivity in response to substrate. Biophysical Journal 103(4): 728-737, 2012

The effect of F-actin on the relay helix position of myosin II, as revealed by tryptophan fluorescence, and its implications for mechanochemical coupling. Biochemistry 43(49): 15404-15417, 2004

Coupling between catalytic site and collective dynamics: a requirement for mechanochemical activity of enzymes. Structure 13(6): 893-904, 2005

Quantum Catalysis in Enzymes: Beyond the Transition State Theory || Quantum Catalysis in B-Dependent Methylmalonyl-CoA Mutase: Experimental and Computational Insights. Philosophical Transactions Biological Sciences 361(1472): 1333-1339, 2006

Mechanochemical interactions in enzymes part 3 the model of enzyme mechanochemical transducer. Studia Biophysica 54(2): 131-138, 1976

Mechanochemical interactions in enzymes. IV. Mechanochemical properties of immobilized preparations of F-actin. Biofizika 21(2): 228-232, 1976

Analysis and interaction of myosin active centers during a mechanochemical cycle. Molekuliarnaia Biologiia 29(3): 662-670, 1995