Electrostatic steering enhances the rate of cAMP binding to phosphodiesterase: Brownian dynamics modeling.
Signaling in cells often involves co-localization of the signaling molecules. Most experimental evidence has shown that intracellular compartmentalization restricts the range of action of the second messenger, 3'-5'-cyclic adenosine monophosphate (cAMP), which is degraded by phosphodiesterases (PDEs). The objective of this study is to understand the details of molecular encounter that may play a role in efficient operation of the cAMP signaling apparatus. The results from electrostatic potential calculations and Brownian dynamics simulations suggest that positive potential of the active site from PDE enhances capture of diffusing cAMP molecules. This electrostatic steering between cAMP and the active site of a PDE plays a major role in the enzyme-substrate encounter, an effect that may be of significance in sequestering cAMP released from a nearby binding site or in attracting more freely diffusing cAMP molecules.
Department of Pharmacology, University of California, San Diego, La Jolla, California, 92093.
Yu-ming M
YM
Huang
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, California, 92093.
Gary
G
Huber
Department of Pharmacology, University of California, San Diego, La Jolla, California, 92093.|Howard Hughes Medical Institute, University of California, San Diego, La Jolla, California, 92093.|Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, 92093.
J Andrew
JA
McCammon
D000242:Cyclic AMP / Q000737:chemistry* / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry* / Q000378:metabolism*; D055672:Static Electricity; D013816:Thermodynamics
D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases
BrownDye simulation; association rate constant; electrostatic property; phosphodiesterase; protein kinase A; second messenger