2014 Workshop Tuesday Lunchtime Discussion

Tuesday Afternoon Discussion: Making free energy calculations robust.

Are we getting the right answers for the right reasons?

• do we get the same answer from different programs? different people? different protocols?

• deviation from X-ray structures may indicate problems? how to quantify?

• evaluate crystal quality beforehand, especially ligand density; automated?

• insufficient number of counterions; poor counterion sampling/decorrelation

• what parts of active site move for ligands in a congeneric series? if a part of the protein we hadn’t seen move before changes conformation, that is potentially a red flag

• infrequent events are bad for convergence; how can we detect them? number of rotamer transitions? MSMs? correlations with dV/dlambda?

• detecting ergodicity problems with simulations we’ve run vs. gross errors vs. setup errors

• compare different community simulation pipelines for same input?

• consistency in thermodynamic pathways / cycle closure / redundancy

• replication of the same simulation, varying things we think don’t matter (e.g. velocities, initial binding modes, water placement, slightly different preps of same protein,

bound vs unbound structure); check consistency

• error bar estimates from multiple replicates of same simulation

• “TurboTax” style warnings and sensible default recommendations

• “Phenix”-style choices for modeling, tailoring options to user

• tooltips are useful for users in setup

• reverse convergence of DeltaG with time

• energy drift or large fluctuations; check energy conservation

• using right method (e.g. can’t use Zwanzig formula if work distribution too large)

• RMSD of protein and ligand

• were motions we expected to sample actually sampled? (e.g. loops)

• time autocorrelation of property you are interested in (simple statistical hygiene)

• need at least N independent data points to have some idea of how things are behaving