 to present our proposed model, we called it a switching force field model as a kind of polarisable model. The aim of this work is a calculation of effective free energy for translocation of drug. Here in this figure you can see the black drug, the translocation of drug from the body environment to the membrane to obtain the barrier of that. And the aim of this work is to concede their effect and the role of environment on a drug, like partial charges for this drug, then to concede their quantum nature of drug. Then the main question of this work is so for this model, which kind of partial charges we need, vacuum as a dielectric constant of 1, like current force field, oil with dielectric constant of 2 as a membrane environment or AT, the environment of the barrier. And also how can we do that and we obtain it? For the first question, it's the answer of that. And I want to show you this pachytaxel, it's anti-cancer drug. And here is the difference of partial charges with dielectric constant of 2 and AT. You can see the difference between these partial charges when we moving from 2 to AT, when we use quantum calculation like DFT to obtain it. And it's very important to consider it. Sorry, could you please hide in this window you have? Oh, yeah, sure. Okay, I should again. Okay. Yeah. Yeah, thank you. Then the motivation of this work is because I've been with trying with data discrepancy for administration of drug and the important role of in silica studies to understand the details of interaction between drug and surrounding like MD simulation, MC or QM to understand details of interaction between them. For example, the membrane of cell for the better modification of drug. And then to become effective polarisable model have been developed. And they are based on the induction of dipole moment like Druth model or FlexQ model, but they're complicated methods and also to the best of my knowledge. So far there is one D-recus study related to translocation of chloroform from the membrane and they did this simulation with different force field from martini to Druth and they got different profile of free energy that the Druth one is more close to experimental results. But what's the challenges also here? It's based on fixed dipole moment and it changed just based on induction of that in the presence of the electric field. And also as all of you know the importance of electrostatic interactions like fundamental for the biosystem and we should consider this type of interaction for our simulation at the most basic level. So to address these challenges we propose our model. Okay, we call it switching force field and now I'm gonna explain more about the details of that. Here we have the drug and it's parameterized the partial charges of that with dielectric constant of AT. It's come from the DFT calculation. Also we have drug in the membrane with the dielectric constant of 2 and with this type of partial charges. And we want to study the translocation of drug from one environment to other one like here. Nigel, I had a question for you. Why is the dielectric constant 2? Is there a justification for it? Or does this come from some experiment or from some simulations or is it assumed to be 2? Yeah, because we know that the membrane upset its oil environment and the dielectric constant of death is the approximation 2. And then we want to consider the partial charge of drug for the force field. We should consider this environment when we do the DFT calculation. I understand you need to do it. What I'm asking is why isn't it 5 or 10 instead? Yeah, because it's like close to experimental condition. So you have a justification for it. Fine, that's it. And then for translocation of death, for example, from water or from membrane to water, they can do that with umbrella sampling, pooling, jars and whatever. And then if also we consider the drugs with other partial charges of another environment like here, we have a difference between the free energies. And now and also here and it's like it's thermodynamic cycle. And using this thermodynamic cycle, how can we obtain our effective profile of free energy? Then we should consider the drug with adhesive state of water. And gradually we should switch to the environment of the membrane with the other partial charges. So what we need now is a coupling parameter as a function of dielectric constant of environment. The best one here is the water density. And using that and also because of the probability density. It's like for the effective one is like a linear combination between the state of drug with partial charges of AT into water and that's one to the membrane. Then based on that, it leads to obtain effective free energy. It's the Boltzmann average of these two states. And then now I'm going to explain details of how we can use it for our model. Here it's the drug is the pachytaxel that I mentioned it's before and the model of membrane is DLPC. Here it's the partial charges of atom of pachytaxel from the DFT calculation. And it's the vertical and horizontal axis of death. It's based on charges and we obtain it and now we have two force fields for that. So this you get from a zero kelvin optimization? First of all, I did the DFT calculation and I obtained optimization structure. And then those charges are obtained? Yeah. And also I use this optimized structure for my MD simulation. The structure is optimized based on DFT calculation out of them to be sure about the accuracy of all of results. Because now it's modern and we need to be sure about all of them. But then in the MD, the drug changes its confirmation, right? Yes. Yes, but just first structure of that to start. Okay, I understand. Yeah. Then it's first of all, we obtain it's a free energy, the barrier of free energy, respect to distance from mid-plane for the translocation of pachytaxel through water to mid-plane of membrane. Here is the mid-plane of membrane. And first we did it with these partial charges and then with the partial charges of the dielectric consent of two. Then we need offset for them based on thermodynamic cycle that I explained it. Then with thermodynamic integration here into pure water, we got the difference between these two estates. Then we shift it. And now to use the model, we need water density. And gradually we can switch from these estates to other one to consider the changing partial charges based on the environment. And the important point that I should mention here, the difference of these lines and translocation free energies in the mid-plane is that we can obtain it here also to compare it with the thermodynamic integration of the drug in the mid-plane of membrane just to be sure about accuracy of translocation free energies. It's like proof for this for this simulation. And here we got the error of that is less than one percent. Then after that we do and we did this simulation for the different common anti-cancer drugs. The Pactitex, PK and Duxor have been seen with different structure, molecular weights and also polar groups and also for the different membrane, DLP, DPPC and POPC with different bending rigidity. And the important message of this work here, this figure, We obtained switching the profile of free energy based on our model, the black one, and also the orange one is based on the normal force field, Charme M36. Just as a control, now you can see the difference between just different magnitude, also sign of them, but it's really up to the structure of the drugs and the combination of the drug and type of lipid interaction. I think someone wants to ask me, no? Okay, then the important message of... Two minutes, please. Two minutes, okay. And now it's the important message of this work here and it really can affect any modification of these drugs to better modification of them, specifically for the chemoresist and state cancer cells and also for lipid membrane trapey. We need to understand the details of interaction. We should use partial charges and switching barrier and for this kind of simulation and for this kind of study. As a summary, I want to again explain about the protocol of this model. We need to obtain a partial charges from QIM calculation. It's a very important step to use. It's really the final result and accuracy of them. It's really up to this step. It's very important. And after that, by consideration, also the dielectric constant for them and also it's another point of that. And then we need to obtain translocation free energy like umbrella sampling for equilibrium condition or like Jarsinski for non-equilibrium condition. But we should do that with two different force fields. Then after that, we need offset between this translocation and thermodynamic integration definitely can help us. For one side, we can obtain it and for another or for other side. I mean, for the pure water or the mid-plane of membrane. But for the pure water, it's very easy because of the sampling of that. It's not really expensive like the mid-plane of membrane. And then we need to test it to be sure about all the steps because now we have thermodynamic cycle. It's like exact. And then just to compare it. And after that, we can obtain effective free energy profile. That's all about that. Then, gradually, attention and thank you. Thank you for your attention. Now I'm ready for all of your questions. And also, I'd like to say that I would be glad if someone interested in this model to, it is my email, to have a deep talk and also if someone wants to get me any comments. Okay. Thank you very much for your talk. We have two questions. I would ask you to be fast. So, Mariam first. Yeah. Yeah, go ahead. Hi. Can you hear me? Yeah. Thanks for the nice talk, Najla. I wanted to ask you now that you applied this new method, your results, how did you compare your results with the experimental values? Like now, the results you obtain, are they similar? Like if you have TACCEL and now your application of the changing force by switching force field, then the binding energy that you obtain is closer to the experiment or it doesn't show a change or it's more different. Is there any comparison with the experiment with your current results? Yeah, yeah, yeah. Thank you. It's like model and this project is just a model to present a model of that, but it's an ongoing project and now we are doing it with experiments also stuff to be sure about that and yeah, for my next presentation. Yeah, but right now it's just model and now, but yeah. There must be some experiments already done, right? Like regardless of what force field you are in. Yeah, no, because the current study is based on like in vitro studies mainly, not really to track the translocation of drug from the membrane, like to see, like to obtain like electron density of that, what's happened during this translocation. They're like just in vitro and like to obtain the cellular uptake of to investigate the cellular uptake of drugs, but now we are doing that and yeah. Okay, I'm looking forward to your next talk. Thank you. Okay, so with this we have to finish. Thank you very much Nazla, again. Yeah, thank you.