Dimerization of surfactant protein C studied through molecular dynamics simulations

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Title: Dimerization of surfactant protein C studied through molecular dynamics simulations
Author: Korolainen, Hanna
Contributor: University of Helsinki, Faculty of Science, Department of Physics
Publisher: Helsingin yliopisto
Date: 2018
Language: eng
URI: http://urn.fi/URN:NBN:fi-fe201804208588
Thesis level: master's thesis
Discipline: Theoretical Physics
Teoreettinen fysiikka
Teoretisk fysik
Abstract: All aerobic organisms require oxygen, which is taken into the lungs from the outside air during inhalation. From the lungs it travels all the way to the alveoli. The lung surfactant inside the alveoli consists of roughly 90% lipids and 10% proteins. Its primary functions are the reduction of the surface tension of the fluid inside the alveoli and its role as a part of the innate immune defense. The four most abundant proteins in the lung surfactant are called SP-A, SP-B, SP-C, and SP-D. The hydrophobic surfactant protein C (or SP-C) is the smallest of the four. It has a primarily α-helical structure with two palmitoylated cysteines attached to the N-terminal, helping SP-C to be bound to the surfactant membranes more tightly. The primary functions of SP-C include the transfer of lipids from lipid monolayers to multilayered structures, the enhancement of the adsorption of surface active molecules into the air-liquid interface, and the maintenance of the integrity of the multilayered structure. Lack of SP-C is known to lead to severe chronic respiratory pathologies. A potential dimerization motif has been suggested to be located near the C-terminus of SP-C. The purpose of this project was to study the possible dimerization of SP-C using the tools of molecular dynamics simulations. In this method Newton's second law is used to calculate the time evolution of the system. The resulted trajectory describes how the positions and velocities of the particles in the system change with time. Both coarse-grained (Martini force field) and atomistic (OPLS force field) models were used in the project. Dimerization was found to occur in coarse-grained simulations of 20 SP-Cs embedded into a bilayer: both aggregation and dissociation of the proteins were observed during a period of 1μs. Excessive aggregation of membrane proteins is known to be a problem when using the Martini force field. However, the dimers in the simulations were not irreversible, which indicates that the usage of the Martini force field was rather well justified. The dimerization motif found in the simulations is largely consistent with the one suggested by experiment. The dimers were also studied through atomistic simulations based on the fine-grained structures of coarse-grained simulations, and the atomistic simulations indicated the dimers to be stable. Altogether, the simulation results are in favor of the view that SP-C exists in a dimeric form. The function of the dimer structure remains to be clarified in future studies.

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