If your starting model of the wild-type complex is good, you can probably get a decent estimate of the mutant structure with ISOLDE. Assuming your model is #1, first restrain everything to the existing geometry with: isolde restrain distances #1 displayThreshold 0.1 isolde restrain torsions #! Then introduce your mutations with swapaa (I recommend `swapaa mousemode` for this because it keeps the sidechain hydrogens). Start a simulation encompassing the interface region, and try to find the most sensible conformation for each mutant site. If you need to, you can selectively release restraints on the currently selected atoms with: isolde release distances sel isolde release torsions sel ... or, if you first do: isolde shorthand then for the rest of the session, you can replace the above with `rd` or `rt` respectively (or `ra` to release both distance and torsion restraints). Best, Tristan On Mon, Jul 24, 2023 at 6:14 PM Eric Pettersen via ChimeraX-users < chimerax-users@cgl.ucsf.edu> wrote:

Begin forwarded message:

*From: *Krishnan Raman <RKrishnan@BIOCRYST.com> *Subject: **depicting contacts* *Date: *July 24, 2023 at 9:50:11 AM PDT *To: *"chimerax-users-owner@cgl.ucsf.edu" < chimerax-users-owner@cgl.ucsf.edu>

Hi all, Any ideas to depict a dramatic improvement(200 nm to femtomolar) in binding affinities before and after mutations(about seven) in chimerax? II have tried contacts , swapaa etc. nothing seems dramatic enough for visuals Thanks

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Elaine, I completely agree with you. Iam trying to make some presentation for nonscientific folks, hence the query. Thanks Krish Sent from Mail<https://go.microsoft.com/fwlink/?LinkId=550986> for Windows From: Elaine Meng<mailto:meng@cgl.ucsf.edu> Sent: Monday, July 24, 2023 2:44 PM To: Krishnan Raman<mailto:RKrishnan@BIOCRYST.com> Cc: ChimeraX Users Help<mailto:chimerax-users@cgl.ucsf.edu> Subject: Re: [chimerax-users] depicting contacts [EXTERNAL] Hi Krish, It is rarely possible to show some kind of obvious visual/structural correlate to energy improvements of a kcal or two from a simplistic approach to virtual mutation such as the sidechain swaps that ChimeraX does. One might need to do a full-scale new prediction of the mutant structure in some other program, or even do a long dynamics simulation (or free energy perturbation simulation with gradual mutation) to gain insights into the contributions to the change in affinity. It might be something quite subtle like changing the conformational entropy of the unbound state. Just my two cents' Elaine ----- Elaine C. Meng, Ph.D. UCSF Chimera(X) team Department of Pharmaceutical Chemistry University of California, San Francisco On Jul 24, 2023, at 10:12 AM, Eric Pettersen via ChimeraX-users <chimerax-users@cgl.ucsf.edu> wrote:

From: Krishnan Raman <RKrishnan@BIOCRYST.com> Subject: depicting contacts Date: July 24, 2023 at 9:50:11 AM PDT

Hi all, Any ideas to depict a dramatic improvement(200 nm to femtomolar) in binding affinities before and after mutations(about seven) in chimerax? II have tried contacts , swapaa etc. nothing seems dramatic enough for visuals Thanks

CONFIDENTIALITY NOTICE This email, including any attachments, may contain confidential or legally privileged information that is intended only for the individual or entity to whom it is addressed. If you are not the intended recipient, please be advised that any dissemination, distribution or copying of this email and any attachment is strictly prohibited. If you have received this email in error, please reply to the sender so that BioCryst Pharmaceuticals, Inc. can take corrective measures and then permanently delete this email and any attachment, including any printed copies. Thank you.