Abstract
Gas sensing is crucial for both prokaryotes and eukaryotes and is primarily performed by heme-based sensors, including H-NOX domains. These systems may provide a new, alternative mode for transporting gaseous molecules in higher organisms, but for the development of such systems, a detailed understanding of the ligand-binding properties is required. Here, we focused on ligand migration within the protein matrix: we performed molecular dynamics simulations on three bacterial (Ka, Ns and Cs) H-NOX proteins and studied the kinetics of CO, NO and O2 diffusion. We compared the response of the protein structure to the presence of ligands, diffusion rate constants, tunnel systems and storage pockets. We found that the rate constant for diffusion decreases in the O2 > NO > CO order in all proteins, and in the Ns > Ks > Cs order if single-gas is considered. Competition between gases seems to seriously influence the residential time of ligands spent in the distal pocket. The channel system is profoundly determined by the overall fold, but the sidechain pattern has a significant role in blocking certain channels by hydrophobic interactions between bulky groups, cation–π interactions or hydrogen bonding triads. The majority of storage pockets are determined by local sidechain composition, although certain functional cavities, such as the distal and proximal pockets are found in all systems. A major guideline for the design of gas transport systems is the need to chemically bind the gas molecule to the protein, possibly joining several proteins with several heme groups together.
Highlights
Gas sensing is an essential and crucial facet of cell signaling, regulating a vast array of cellular and physiological functions including respiration, cytoprotection, gas storage, neurotransmission, inflammation, gene transcription and cardiovascular homeostasis [1,2,3,4]
We aim to answer the following questions: (1) How similar are the kinetics of the diffusion of the various gases in the studied proteins? (2) Is it sufficient to consider the direct route for ligand entrance/exit OR should the tunnel system be taken into account? (3) Are the channels specific to the fold
H-NOXs) OR matrix specific? (4) Are the ligand-binding pockets selective toward specific ligands, and if so, is this selectivity created by the local sidechain pattern or the global fold? (5) What kind of guidelines can be given for the design of nitric oxide (NO)/carbon monoxide (CO)/O2 -specific H-NOX transport systems in terms of pockets/cavities?
Summary
Gas sensing is an essential and crucial facet of cell signaling, regulating a vast array of cellular and physiological functions including respiration, cytoprotection, gas storage, neurotransmission, inflammation, gene transcription and cardiovascular homeostasis [1,2,3,4]. Nitroglycerol, a compound capable of releasing NO, has been used for more than a century for the treatment of angina pectoris, its mode of action was not understood for long. This example highlights the therapeutic potential of small signaling molecules, but their clinical use has remained limited due to their gaseous nature, extensive reactivity, short half-life and systemic toxicity [7,8].
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