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Operating Mechanism and Molecular Dynamics of Pheromone-Binding Protein ASP1 as Influenced by pH
Odorant binding protein (OBP) is a vital component of the olfactory sensation system. It performs the specific role of ferrying odorant molecules to odorant receptors. OBP helps insects and types of animal to sense and transport stimuli molecules. However, the molecular details about how OBPs bind or release its odorant ligands are unclear. For some OBPs, the systems' pH level is reported to impact on the ligands' binding or unbinding capability. In this work we investigated the operating mechanism and molecular dynamics in bee antennal pheromone-binding protein ASP1 under varying pH conditions. We found that conformational flexibility is the key factor for regulating the interaction of ASP1 and its ligands, and the odorant binds to ASP1 at low pH conditions. Dynamics, once triggered by pH changes, play the key roles in coupling the global conformational changes with the odorant release. In ASP1, the C-terminus, the N-terminus, helix α2 and the region ranging from helices α4 to α5 form a cavity with a novel ‘entrance’ of binding. These are the major regions that respond to pH change and regulate the ligand release. Clearly there are processes of dynamics and hydrogen bond network propagation in ASP1 in response to pH stimuli. These findings lead to an understanding of the mechanism and dynamics of odorant-OBP interaction in OBP, and will benefit chemsensory-related biotech and agriculture research and development.
Olfactory sensation is an essential capability for insects and mammals, enabling them to detect stimuli in the surroundings for prey, survival and reproduction [1], [2]. In the chemical-to-sensation process, odorant binding proteins (OBPs) ferry small, primarily hydrophobic odorant and/or pheromone molecules through sensillar lymph to olfactory receptors (ORs), triggering a cascade of chemosensory events which lead to activate sensory neurons [3], [4]. Signaling chemical molecule perception is particularly vital for many insects, such as social insect like honey bees, where the queen groups and controls the individual behaviors using sophisticated pheromone communication. Many studies have attempted to determine the key residues for OBP ligand recognition [5], binding and releasing [6]–[10]; however, the OBP's roles in delivering odorants has caused extensive debate [4], [11]. Therefore, the mechanism and dynamic pathways on how OBP binds and releases pheromones in vivo need to be explored at molecular level. An atom-level dynamics understanding of OBPs' binding and unbinding of odorant ligands, especially how pH affects the interactions between OBPs and their ligands, will help us understand the operating mechanism and functions of OBPs, ORs and the chemosensory system. This will assist with disease prevention, pest-control [12], food processes and agricultural technologies [1], [12].
The initial steps of chemo-sensing in honey bees involve the pheromone binding proteins (PBPs, one sub-type of OBP) binding to pheromone molecules, and carrying these ligands to ORs so as to activate ORs [3]. To date the accepted mechanism, as revealed by the crystal structures [7], [13]–[15] (see Fig.1), is that the process of OBP binding and releasing pheromone is to some degree pH-dependent. The same PBP and their ligands can be crystallized either in apo (ligand-free) or holo (ligand-bound) states subject to varying pH. Meanwhile, in an aqueous environment, there are different conformational states of the same protein at different pH [14]. In addition to honey bees, BmorPBP1 (PBP from Bombyx mori) structures show that the C-terminal loop is an important region in the presence of changing pH conditions [13], [14]. When BmorPBP1 is exposed to low pH condition (e.g. pH = 4.5), the C-terminal loop forms a new helix towards the binding cavity and pushes the odorant ligand out of the cavity. Conversely, at neutral pH condition (e.g. pH = 6.5), the unstructured C-terminus (C-ter) extends into the solvent and opens the binding cavity to host the ligand. Similar to BmorPBP1, ApolPBP (PBP from the giant silk moth Antheraea polyphemus) and AtraPBP1 (PBP from the navel orange worm Amyelois transitella) have the same long and unstructured C-ter as BmorPBP1, sharing a similar same mechanism in response to pH changes [16]–[18]. Unlike BmorPBP1, ASP1 (PBP from honeybee Apis mellifera) [19], AgamOBP1 (OBP from the malaria mosquito Anopheles gambia) [20], AaegOBP1 (OBP from the yellow fever mosquito Aedes aegypti) [21] and CquiOBP1 (OBP from southern house mosquito Culex quinquefasciatus) [9] do not contain a long loop at their C-termini, but their short loop could also fold into the binding cavity, occupy the binding site and disrupt the ligand's entry.
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110565
 
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