I'm designing a covalent inhibitor on an in silico study. Should I use the "pre-reaction" non-covalent ligand-protein complex or covalently bonded one on the Molecular Dynamic simulation input?
I think it's necessary to know how long the ligand stays in the binding site before the colavent-bond-forming reaction occurs. While it is probably a femtoseconds-process that does not need such nanoseconds stability. So it is more beneficial to do MD on the covalent-bonded complex to evaluate how strong its resident time is (and the inhibitory potential). The TS-DFT calculation suggests that the covalent bond may be reversible. However, I am not sure that MD can represent bond-breaking reactions. I still haven't gotten any concrete data on how several studies did it. Please give me your opinion. Thanks
Hello,
It depends on the question you want to answer. If you think that the orientation/conformation of the ligand in the pocket is important before the reaction, then standard MD might be useful. But if you have a bond formation that is primarily diffusion-limited, or occurs at the few-femtosecond timescale, I don't know how much information you could get from a standard MD simulation.
If your interest is the chemical reaction as such, standard MD definitely cannot help you, since it is not possible to model bond breaking and bond formation. For that, you should use more specialized techniques where you model the catalytic site at the quantum mechanical level. For example QM/MM.
Good luck!
Thank you so much! Your answer was very helpful for my research.
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