Browsing by Subject "Molecular dynamics simulation"

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Open Access
Investigation of human IL18 structures towards understanding the dynamics and self-assembly of IL18-IL18BP heterodimers
(2023-08) Yazıcı, Yılmaz Yücehan
Interleukin-18 (IL18) is an inflammatory cytokine involved in the regulation of both innate and adaptive immunity. IL18 activity is tightly regulated by its constitutively secreted inhibitor, IL18 binding protein (IL18BP). All known IL18BPs from human to poxviruses share an identical protein fold. Investigation of known crystal structures of human IL18 illustrated that the region between the 68th and 81st amino acids is either missing or disordered in all IL18-IL18BP complexes while adopting a 310 helical structure in the free or signaling complexes of IL18. The C74 residue in this region was reported to form a novel intermolecular disulfide bond in the human IL18-IL18BP tetrameric assembly. Yet, the impact of this small surface epitope on the stability and self-assembly of IL18 is unclear. First, we investigated the dynamics of this small surface region of IL18-IL18BP heterodimers by molecular dynamics simulations. In simulations, we used all known crystal structures of IL18-IL18BP and two additional computer models generated by AlphaFold2 and homology modeling to observe the differential folding of small surface regions. Next, we generated the proposed human and Yaba-like disease virus tetramers and analyzed them with or without intermolecular disulfide bonds. We found that the helical structure of small surfaces stabilizes the backbone of the complex through reducing its flexibility. While our computational model folded into a more stable and less flexible short IL18 epitope, similar to free IL18 or bound IL18 on the signal complex, IL18 from the complexes with human or virus IL18BPs displayed flexible regions with a less stable backbone. The core of the human crystal loosened, becoming more exposed to solvent in the human crystal structure. Particularly, a salt bridge stabilized the human IL18 structure at the helix configuration, linking the helix to the core region. We observed that the bivalent binding mode for the human tetramer, which is disturbing one side of the tetramer by breaking the disulfide bonds, did not affect the stability of the complex, and thereby the tetramer remained intact. Hence, the tetramer formation of IL18-IL18BP can be beneficial to the host as it provides an additional stability advantage. Overall, our results show that the short IL18 epitope between the amino acids 68 and 81 mediates stability and self-assembly of IL18-IL18BP heterodimers.
Open Access
Retinal proteins as model systems for membrane protein folding
(Elsevier BV, 2014) Tastan, O.; Dutta, A.; Booth, P.; Klein-Seetharaman, J.
Experimental folding studies of membrane proteins are more challenging than water-soluble proteins because of the higher hydrophobicity content of membrane embedded sequences and the need to provide a hydrophobic milieu for the transmembrane regions. The first challenge is their denaturation: due to the thermodynamic instability of polar groups in the membrane, secondary structures in membrane proteins are more difficult to disrupt than in soluble proteins. The second challenge is to refold from the denatured states. Successful refolding of membrane proteins has almost always been from very subtly denatured states. Therefore, it can be useful to analyze membrane protein folding using computational methods, and we will provide results obtained with simulated unfolding of membrane protein structures using the Floppy Inclusions and Rigid Substructure Topography (FIRST) method. Computational methods have the advantage that they allow a direct comparison between diverse membrane proteins. We will review here both, experimental and FIRST studies of the retinal binding proteins bacteriorhodopsin and mammalian rhodopsin, and discuss the extension of the findings to deriving hypotheses on the mechanisms of folding of membrane proteins in general. This article is part of a Special Issue entitled: Retinal Proteins - You can teach an old dog new tricks.
Open Access
Surface adsorption of co-polymers
(2022-08) Karimpour Khamaneh, Darya
Since the Polymer Age was born, researchers have manifested a great interest in investigating polymeric world. Such an enthusiasm arises from polymers’ astonishing proper- ties and the sign of their footprint in various places and natural phenomena. Studying the structure of these long molecules of repeating identical units makes a better insight of their mechanisms. Besides, discovering the fact that how polymers enroll in numerous natural events creates a huge opportunity for scientists to mimic their mechanisms in synthetic (human-made) processes or to improve their functions. So far, multitude of models and approaches have been utilized to investigate polymers. Here, we employ molecular dynamics simulations, where we model surface adsorption of co-polymers. The motivation behind this study is to examine if different physical and chemical criteria including initial conditions, chemical structures, and reference frames can have impact on copolymers’ adsorption. Our simulations qualitatively indicate that different co-polymers get adsorbed on the surface. Furthermore, using the data extracted from simulations, we analyze modification of monomers’ concentrations while co-polymers get adsorbed on the surface. We, also, quantify changes of brush height, and creation of loops on the surface. Then, by replacing di-block co-polymers (the first type of co-polymers for our model) with tri-block, random, and alternating co-polymers, also homopolymers, we analyze parameters and reach to distinct patterns for each type of linear co-polymers. In another attempt, we modify strength of interactions to investigate possible impacts of solvent on adsorption process. For the last step, we try to alter the arrangement of co-polymers on the surface, and this time, measure the same parameters and compare results with the previous configuration. We think this study to cascade into more aspects of surface-adsorption of co-polymers, and, in an extensive view, to have implications in the creation of insight into biological phenomena, and/or the biotechnological research and applications.