Hi all,

I'm running into a persistent issue in ISOLDE and would appreciate any guidance, especially from Tristan if he has a moment.

ChimeraX version: 1.12 OS: Windows

Summary: isolde sim start fails immediately with no simulation actually running, for essentially any selection in my model -- not just one problem region. The log shows:

Sim termination reason: None ISOLDE: stopped sim

with no further error detail, immediately after the residue templates (FAD, P6G, PO4) finish loading from the internal database.

What I've ruled out so far:

Not a stuck/lingering Unparameterised Residue widget (confirmed via full ChimeraX restart)
Not specific to one problem residue -- originally isolated a specific residue (ASN, chain A) via bisection, but after fixing it (full atom+bond rebuild from a working homologous chain, confirmed via distance checks that backbone geometry was reasonable), the same failure then appeared in a completely unrelated, previously-working region of the model
Not a duplicate-atom/clash issue -- scanned for overlapping atoms (<0.6 A) in the affected region, found and removed a set of stray duplicate hydrogens, confirmed zero overlaps remaining; simulation still failed
Not an mmCIF metadata issue -- the same region on the model's other (homodimer) chain simulates without any problem
Not a session-state/cache artifact -- fails identically after closing ChimeraX entirely and reopening a freshly saved PDB from disk
Not a simulation fidelity/resource issue -- tested at Medium/Medium and Lowest/Fastest, identical failure both times
Not resolved by a full OS-level restart (not just closing ChimeraX) -- identical failure immediately after reboot, on a select /A:60-61 range that had previously worked earlier the same day
Not resolved by reinstalling the ISOLDE bundle via the ChimeraX Toolshed and restarting -- identical failure persists on previously-failing selections (/A:508-518, /A:60-86) immediately after reinstall; only the one range that had always worked (/A:60-61) "worked," which isn't diagnostic since it never failed in the first place

Sequence that reproduces it (after a clean restart):

open session_backup_03.cxs isolde start clipper associate #1.1.1.1 toModel #1.2 select /A:508-518 isolde sim start /A:508-518

Result: templates load (FAD/P6G/PO4), then immediate "Sim termination reason: None."

The Problem Zones tab is empty, which I believe is expected since no simulation has ever successfully started to generate restraint data.

Model contains a protein homodimer (two chains, otherwise identical) plus FAD, PO4, and P6G heteroatoms, refined via Servalcat from a cryo-EM map. Happy to share the model/map files if useful for reproducing this.

Any guidance on what else to check (OpenMM installation, platform/GPU selection, log verbosity settings for more detail than "None") would be much appreciated

John Guardado (he/him) | G1 PhD Student, BM

CALIFORNIA INSTITUTE OF TECHNOLOGY