APR pull direction

[mauramalinka01]

Hello,
I am using APR script for cucurbiut[7]uryl and I love it:)

I have used it for ligands that are bigger (part of the ligand is outside of the host) and there is no doubt which direction should the script use as a pull direction. Now I have a case that ligand is inside and from a geometrical point of view, both directions of the pull are possible.

Question is, does it matters what pull direction I choose and I should perform both and the correct one is the one with lower energy?

The pull direction is not important, but why. It's because cucucubit[7]uryl is symmetrical (it has horizontal mirror plane). Or, it generally doesn't matter?

Thanks.

[mkgilson]

Hi, Thanks so much for your positive comment! Someone else may already have replied, but here is my 2 cents. In principle, it doesn't matter which direction you choose because free energy is a state function-- the change in free energy is independent of path. So either path from bound to unbound should give the same free energy difference. This is true whether or not the host and guest are asymmetric. That said here are two other points (that you are probably already aware of!): 1) the efficiency of numerical convergence could be different in the two directions, such as if one direction requires forcing a bulky group out of the small CB portal and the other direction doesn't 2) for an asymmetric guest in an asymmetric host (such as a cyclodextrin instead of a CB), the pulling path still doesn't matter, but it's important to consider both binding orientations. There's a simple way to do this if you want to learn more. Best regards, Mike On 10/6/2021 4:50 AM, mauramalinka01 wrote: Hello, I am using APR script for cucurbiut[7]uryl and I love it:) I have used it for ligands that are bigger (part of the ligand is outside of the host) and there is no doubt which direction should the script use as a pull direction. Now I have a case that ligand is inside and from a geometrical point of view, both directions of the pull are possible. Question is, does it matters what pull direction I choose and I should perform both and the correct one is the one with lower energy? The pull direction is not important, but why. It's because cucucubit[7]uryl is symmetrical (it has horizontal mirror plane). Or, it generally doesn't matter? Thanks. — You are receiving this because you are subscribed to this thread. Reply to this email directly, view it on GitHub<https://urldefense.com/v3/__https://github.com/GilsonLabUCSD/APR/issues/8__;!!LLK065n_VXAQ!21JdZAr2BTZo-XlMVKVL_YmOnijwX6Z7ShjcSWiX8M1eXuJeF2qtCTlCXAC6T6o_RA$>, or unsubscribe<https://urldefense.com/v3/__https://github.com/notifications/unsubscribe-auth/AEAQSQHRAEBZR2JI3MZVYH3UFQZW3ANCNFSM5FOLLIGQ__;!!LLK065n_VXAQ!21JdZAr2BTZo-XlMVKVL_YmOnijwX6Z7ShjcSWiX8M1eXuJeF2qtCTlCXAAEBQQS3A$>. Triage notifications on the go with GitHub Mobile for iOS<https://urldefense.com/v3/__https://apps.apple.com/app/apple-store/id1477376905?ct=notification-email&mt=8&pt=524675__;!!LLK065n_VXAQ!21JdZAr2BTZo-XlMVKVL_YmOnijwX6Z7ShjcSWiX8M1eXuJeF2qtCTlCXABIZi9_mw$> or Android<https://urldefense.com/v3/__https://play.google.com/store/apps/details?id=com.github.android&referrer=utm_campaign*3Dnotification-email*26utm_medium*3Demail*26utm_source*3Dgithub__;JSUlJSU!!LLK065n_VXAQ!21JdZAr2BTZo-XlMVKVL_YmOnijwX6Z7ShjcSWiX8M1eXuJeF2qtCTlCXAC7LfRSnQ$>.

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-- Michael K Gilson, MD, PhD Professor and Chair in Computer-Aided Drug Design Skaggs School of Pharmacy and Pharmaceutical Sciences UC San Diego 9500 Gilman Drive MC0751 La Jolla, CA 92093-0751 858-822-0622 gilson.ucsd.edu bindingdb.org Twitter: @MichaelKGilson

[mauramalinka01]

Hi,

I was thinking the same way. Good to have confirmation.

I'd like to know how to consider both directions in the simulation. Thank you.