Abstract
Although lung surfactant protein B (SP-B) is an essential protein that plays a crucial role in breathing, the details of its structure and mechanism are not well understood. SP-B forms covalent homodimers, and in this work we use all-atom molecular dynamics simulations to study dimeric SP-B’s structure and its behavior in promoting lipid structural transitions. Four initial system configurations were constructed based on current knowledge of SP-B’s structure and mechanism, and the protein maintained a helicity consistent with experiment in all systems. Several SP-B-induced lipid reorganization behaviors were observed, and regions of the protein particularly important for these activities included SP-B’s “central loop” and “hinge” regions. SP-B dimers with one subunit initially positioned in each of two adjacent bilayers appeared to promote close contact between two bilayers. When both subunits were initially positioned in the same bilayer, SP-B induced the formation of a defect in the bilayer, with water penetrating into the centre of the bilayer. Similarly, dimeric SP-B showed a propensity to interact with preformed interpores in the bilayer. SP-B dimers also promoted bilayer thinning and creasing. This work fleshes out the atomistic details of the dimeric SP-B structures and SP-B/lipid interactions that underlie SP-B’s essential functions.
Highlights
Lung surfactant (LS) is a complex mixture of lipids and proteins that is essential to life [1,2,3,4,5,6,7,8]
Another two simulations were composed of two POPC lipid bilayers, with dimeric surfactant protein B (SP-B) initially positioned between the bilayers, with SP-B in a closed (Figure 2c) or open (Figure 2d) conformation, termed Closed Out Two Bilayers (CO2) and Open In Two Bilayers (OI2), respectively
Dimeric SP-B maintained a helicity of 27–35% in all the systems, which is consistent with experiment [29], and demonstrated a variety of other structural features important for promoting non-planar lipid structures, including the probing central loop and the flexible hinge between the two pairs of helices (Figure 1)
Summary
Lung surfactant (LS) is a complex mixture of lipids and proteins that is essential to life [1,2,3,4,5,6,7,8]. Connections between the monolayer and multilayers are critical to function throughout the breathing cycle, which entails an expansion of the surface during inhalation, and contraction during exhalation. Both processes involve the transfer of LS material between the monolayer and the multilayer reservoir, and the hydrophobic LS proteins are critical to these structural transformations. The lipid component is highly enriched in dipalmitoylphosphatidylcholine (DPPC), a zwitterionic phospholipid with two saturated acyl chains that is capable of forming a tightly packed structure This capacity for tight packing means that DPPC can withstand the surface tension at the air/water interface, helping to resist alveolar collapse during expiration [9]. The absence of SP-C is not fatal, its loss does lead to lung mechanics abnormalities [18]
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