 So can you see my screen now yeah, it's coming. Yeah, it's here Doesn't go to the presentation mode Well, I can't fool a screen Sorry, I can't fool a screen the the slides. I don't know one The foolish Maybe start the presentation then is it full of screen now No, I see your floor at your browser window So maybe just your presentation and then share your screen and select the window where you have your presentation open Okay, give me a second Now I should work does it work now Do you see the first slide? Yes now now it works, please go ahead So hello everyone. My name is Mariam as Raul just said I am a computational biologist by education and my research is mainly focused on Molecular dynamics of biomolecules. I did a PhD at non-young technological University of Singapore and My postdoc training was mainly at Sharif University of Technology on the research study supervision I recently became an assistant professor at Shahid Bajdi University So today I'm going to talk about my ongoing project on the immune response You might think that this is a sarcastic title but it's not because I'm going to talk about the molecular mechanism of Immune response in the presence of sugar moieties. So it is in fact a sweet talk I have one family of cytokines play critical roles in triggering the immune response in several conditions such as injury infection and stress and in more serious situations such as cancer and arthritis Because of these important roles, they have been the center of attention for many Experimental and computational studies recently and we used And we looked at the molecular functioning with molecular dynamic simulations So I will briefly mention how they've worked in the cell IL-1 family of cytokines has 11 members and they bind to the receptor to the signaling receptor IL-1 receptor type 1, IL-1 or 1 on the cell surface To send signals to the cell. IL-1 or 1 Contains an extracellular domain that here is shown that it has three subdomains in its extracellular domain here. They are shown in red yellow and Red blue and yellow and they are connected by two linkers and IL-1 or 1 also contains a transmembrane domain and in intracellular TiR domain. What happens is that a cytokine binds to the extracellular domain of IL-1 or 1 Two subdomains, the 1 and the 3 of the extracellular domain and this interaction leads to conformational changes that facilitate binding of the IL-1 receptor accessory protein that is A protein, a transmembrane protein similar to IL-1 or 1 in a structure and in shape and then forms the Functional assembly that sends signals and triggers the immune response That mechanism of action and ligand binding has been explained by several extra crystal structures But one critical factor was missing in that mechanism And that was the extracellular domain of IL-1 or 1 is decorated with sugars or glycans in vivo And these glycans are shown has been shown to play critical roles in IL-1 or 1 Functioning, but they were mainly not considered In this in all the studies. So the process of Attachment of sugars or glycans or carbohydrates to IL-1 or 1 is an enzymatic process known as glycosylation and You can see it's role here in protein folding the stability Trafficking the gun binding et cetera So I used molecular dynamic simulations to model the glycosylated IL-1 or 1 In two different states in the APOL when there is no ligand bound and in the IL-1 beta bound That is the agonist ligand bound to the IL-1 or 1 and studied the conformation and dynamics Etc. All the simulations I presented here or our full atom simulations and I have carried them out With amber package So our simulations showed that the glycosylated IL-1 or 1 the distance between center of masses of two subdomains subdomains 1 and 3 of The IL-1 or 1 decreases upon glycosylation you can show here and the receptor adapts a compact conformation At the right side of the plot The bottom figure is the compact conformation and this dashed line shows the The value the distance value between D1 and D3 in the compact conformation crystal structure also Cross-correlation matrices of the two systems shows that there are more Anticorrelated motions between D1 and D3 upon glycosylation So the receptor mainly adapts the compact form then we asked so how does the glycosylated IL-1 or 1 Binds to IL-1 beta that it's the basically stimulating ligand in the cell Binding free energy between IL-1 beta that is the agonist and IL-1 or 1 In the unglycosylated form of IL-1 or 1 that is shown with blue bars and the partially Glycosylated IL-1 or 1 that is shown with red bars and the fully glycosylated IL-1 or 1 does not change a meaningful Difference between the binding energy. So we concluded that glycosylation does not directly affect IL-1 beta IL-1 binding, but it can indirectly Regulate this process by maintaining the IL-1 or 1 in the compact conformation Then IL-1 or 1 is in the compact conformation the binding site is occluded So it cannot bind to any cytokine. So it's it reduces that it's binding affinity to IL-1 or 1, but not directly and Aside from the rule of glycans in the in the dynamics of the extended and compact conformation of IL-1 or 1 and the rule of IL-1 cytokines binding to it another that we studied so far another important factor To forms the functional assembly in binding is binding of the receptor accessory proteins Here I carried out again conventional and accelerated molecular dynamics to study the rule of The interaction of IL-1 receptor accessory protein with the compact and extended IL-1 or 1 so Here we showed that the compact the complex of compact IL-1 or 1 that is here shown in magenta With IL-1 or scp is very abiding here You can see the final conformations from my MD simulations of the compact complex and you can see that IL-1 or 1 mainly remains compact and most proteins are fully glycosylated so we call this the non-signaling complex again because the IL-1 cytokine binding site is occluded and the distance plots between sub domain tree of IL-1 or 1 extracellular domain and IL-1 or scp keeps a very stable and distance value in all my simulations the blue plots and application of accelerated MD that you can see the results in blue and red plots only led to more dynamic More stable dynamics. So the compact complex will remain compact in our simulation and it's non-signaling and Another sense of simulations was where I Beat the dynamics for the extracellular domain of IL-1 or 1 in the extended form in complex with IL-1 or scp Here I I observed that extended complex seems to be locked in the extended form by the by the Interaction from the two interconnected like hands meaning if you look at here The two like hands from the two proteins make contacts with the other protein and basically keep the signaling Keep the signaling extended Conformation in the extended form If I want to summarize this part, so we showed IL-1 or 1 forms two types of Assemblies one is the compact one that you can that you can show you can see its formation in figures One in figures a and b and this is a non signaling complex And it can act as a down regulatory mechanism for IL-1 or 1 functioning and the immune response That's are connected to IL-1 or 1 Signaling and another and it also forms another signaling Complex or assembly that is formed by extended IL-1 or 1 and the IL-1 or scp. You can see its formation in In figures C and D and then binding so because it's extended then the cytokine here I want to talk and by straight and then does it can triggers the signals to the cell and leads to in your response in our body So so far we have a studied glycosylation Binding of IL-1 beta to eat and how the accessory protein binding leads to formation of two types of assemblies But to complete this picture There is another important factor and that is a homologous Receptor very similar to shape 12 on our one that's called interleukin 1 receptor type 2 I'll one or two again has three immunoglobulin like soft domains in the extracellular domain Same as I'll one or one it is glycosylated and interesting thing It can binds to the same sets of cytokines even with higher affinity on the cell But it misses the intracellular TIR domain So it can bind to the ligands on the extracellular, but it cannot send any signal to the cell And we wanted to see how this one or two compete with our one or one on the cell surface to regulate the immune response this board was done in collaboration with Nargis Jamshidi who is msc students in Dr. Shadi's lab and So we are going to study this Nargis showed that Nargis showed that The island of the island or two upon glycosylation is maintained in the extended form Compared to the unlike oscillator from the plot shows the radius of gyration for I'll one or two Average over all simulations and you can see that's the one or two mainly remains in the extended form This is the opposite of what we have observed for I'll one or one And as I'll one or two can bind to the same sets of cytokines with higher binding affinity Then it suppresses the immune response basically if I want to summarize all of our observations in one sentence I can say that increase of the blood increase of the blood sugars increase of the level of blood sugar could lead to suppression of the I'll one or one involved Immune response because of the keeping the I'll one or one in a compact conformation and thus suppressing the immune response by basically suppressing its ligand binding and by Increasing the binding affinity of I'll one or two to the same sets of cytokines It that I want to thank research Shadi for his continuous support in the last two years Nargis who provided the figure and the plots for the last part of the talk I am also thankful to Shadi Rahma who is a PhD student of Dr. Shadi's lab And she collaborates with me on the projects on the role of blood cans in sauce code to infectivity I didn't mention the projects because of the time here and we are all grateful to Sharif high performance computing center We're providing the computational resource of this work and to you of course for your attention. I am happy to take your questions That's it Okay, thank you very much Maria for your talk and for being in time. So we have time for some questions couple of questions. So Please There are no questions I guess there was too much of biology in it People here are all physicists I have something Okay Now I have a cure. I have a curiosity Okay. Yeah, so so thanks for your talk. So the In the glycosylation is there there's the sugar form Is there a chemical reaction that happens with the protein or what exactly happens there? So what happens is I couldn't explain it much Can you see the slides or not? Yeah, yes. So these are the typical sugars, let's say From the from the left from the left figure. This is the most simple one for example This one in the When your protein is built up, basically you have a polypeptide and it's it has to have a 3d fold, right? When the 3d fold is being it calls It's called translation and after the translation is done There are some decoration occurring on different proteins One of the most famous decorations is attachment of these glycans and this is certainly an enzymatic activity Usually it it occurs with the all or trans phrase glycosyl trans phrase that it's an enzyme that uses ATP in the cell to attach these Blocks of sugars to different specific sites on your protein Okay And these sites are mentioned here. There should be a motif for it The motif is where you have an asparagine you have any amino acid except proline and then you have serine or trione So this is the motif, but this is not a most rude. Sometimes it make it decorated. Sometimes it may not So so I mean just a general the current force fields designed and able to handle Here all the glycans are presented by glycam 06 force field that is Basically the most the most Established full atom force field for the glycans that I am aware of and all the protein residues are presented by amber force field I see. All right. Thanks You're welcome Okay, so thank you very much. Mariam. We have no more time for questions Thank you. Thanks again. So we Asked to the next speaker who is