Elucidating Nitric Oxide Synthase Domain Interactions by Molecular Dynamics
Overview
Affiliations
Nitric oxide synthase (NOS) is a multidomain enzyme that catalyzes the production of nitric oxide (NO) by oxidizing L-Arg to NO and L-citrulline. NO production requires multiple interdomain electron transfer steps between the flavin mononucleotide (FMN) and heme domain. Specifically, NADPH-derived electrons are transferred to the heme-containing oxygenase domain via the flavin adenine dinucleotide (FAD) and FMN containing reductase domains. While crystal structures are available for both the reductase and oxygenase domains of NOS, to date there is no atomic level structural information on domain interactions required for the final FMN-to-heme electron transfer step. Here, we evaluate a model of this final electron transfer step for the heme-FMN-calmodulin NOS complex based on the recent biophysical studies using a 105-ns molecular dynamics trajectory. The resulting equilibrated complex structure is very stable and provides a detailed prediction of interdomain contacts required for stabilizing the NOS output state. The resulting equilibrated complex model agrees well with previous experimental work and provides a detailed working model of the final NOS electron transfer step required for NO biosynthesis.
Astashkin A, Gyawali Y, Jiang T, Zhang H, Feng C J Biol Inorg Chem. 2024; 29(6):611-623.
PMID: 39136772 PMC: 11390318. DOI: 10.1007/s00775-024-02068-8.
Singh S, Gyawali Y, Jiang T, Bukowski G, Zheng H, Zhang H J Biol Inorg Chem. 2024; 29(2):243-250.
PMID: 38580821 PMC: 11181464. DOI: 10.1007/s00775-024-02046-0.
Interdomain Interactions Modulate the Active Site Dynamics of Human Inducible Nitric Oxide Synthase.
Tumbic G, Li J, Jiang T, Hossan M, Feng C, Thielges M J Phys Chem B. 2022; 126(36):6811-6819.
PMID: 36056879 PMC: 10110350. DOI: 10.1021/acs.jpcb.2c04091.
He Y, Haque M, Stuehr D, Lu H Biophys J. 2021; 120(23):5196-5206.
PMID: 34748763 PMC: 8715171. DOI: 10.1016/j.bpj.2021.11.001.
Use of Computational Biochemistry for Elucidating Molecular Mechanisms of Nitric Oxide Synthase.
Bignon E, Rizza S, Filomeni G, Papaleo E Comput Struct Biotechnol J. 2019; 17:415-429.
PMID: 30996821 PMC: 6451115. DOI: 10.1016/j.csbj.2019.03.011.