I have a doubt on in-silico modeling. I want to cyclize a linear peptide sequence by in silico. Which is more favorable method I don't understand. There is 2 pathways-
1. I can cyclize a linear peptide sequence first, after that I can mutate them to increase the binding affinity.
Or, 2. I can mutate the linear sequence first, then I can cyclize the final confirmation. Which method is more preferable, can anyone please answer? I'm confused like which method is more reliable?
If I cyclize the sequence first, is there any chance that when I will do mutation, the confirmation will not change so much. Is it better way or not to increase the binding energy?
Thanks in advance for any kind of help.
Hi Pousali,
I would use cyclization after mutation.
I assume that many theoretical chemists recommend the reverse, but please consider which case is the more plausible and try the shoes of an experimental chemist.
a) If you can preparatively perform the mutation in the cyclized version (I have doubts about it), then you can use the post-cyclization version in modeling.
b) But, usually, the mutation occurs in the linear version, followed by the cyclization. However, it may result in a slightly different macrocycle conformation.
Of course, MD simulations can reveal that a priori or post-modification provides the lowest energy conformation.
Please also note that for macrocycles, the energy surfaces may be very flat but not traversable by the optimizer, i.e., the optimized geometries are different while the energy differences are insignificant. MD methods can also help to overcome this problem.
Good luck,
Laszlo
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