Skipping a lambda state in ABFE due to incorrect alchemical definition

[MartinFuentetaja]

Dear all,

I would like to ask whether it is possible to skip a lambda state in an ABFE calculation performed with YANK.

To provide some context, I have already completed ABFE simulations using the following alchemical scheme:

Complex phase:

        alchemical_path:         #0     1     2     3     4     5     6     7     8     9     10    11    12    13    14    15    16    17    18    19    20    21    22    23    24    25    26    27    28    29    30    31    32    33    34    35    36    37    38    39    40    41    42    43     44    45    46     47     48    49     50    51     52    53     54    55     56    57     58    
        
        lambda_restraints:     [0.00, 0.01, 0.03, 0.05, 0.07, 0.10, 0.20, 0.40, 0.60, 0.75, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.000, 1.00, 1.000, 0.00, 1.000, 1.00, 1.000, 1.00, 1.000, 1.00, 1.000, 1.00, 1.000, 1.00, 1.000, 1.00]

        lambda_electrostatics: [1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 0.95, 0.90, 0.85, 0.80, 0.75, 0.70, 0.65, 0.60, 0.55, 0.50, 0.45, 0.40, 0.35, 0.30, 0.25, 0.20, 0.15, 0.10, 0.05, 0.00, 0.00, 0.00, 0.00, 0.00, 0.00, 0.00, 0.00, 0.00, 0.00, 0.00, 0.00, 0.00, 0.000, 0.00, 0.000, 0.00, 0.000, 0.00, 0.000, 0.00, 0.000, 0.00, 0.000, 0.00, 0.000, 0.00, 0.000, 0.00]

        lambda_sterics:        [1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 0.95, 0.90, 0.85, 0.80, 0.75, 0.70, 0.65, 0.60, 0.55, 0.50, 0.45, 0.40, 0.375, 0.35, 0.325, 0.30, 0.275, 0.25, 0.225, 0.20, 0.175, 0.15, 0.125, 0.10, 0.075, 0.05, 0.025, 0.00]

Solvent phase:

      alchemical_path:         #0     1     2     3     4     5     6     7     8     9     10    11    12    13    14    15    16    17    18    19    20    21    22    23    24    25    26    27    28    29    30    31    32    33    34     35    36     37    38     39    40     41    42    43    44        
        
      lambda_electrostatics: [1.00, 0.97, 0.93, 0.90, 0.85, 0.80, 0.75, 0.70, 0.65, 0.60, 0.55, 0.50, 0.45, 0.40, 0.35, 0.30, 0.25, 0.20, 0.15, 0.10, 0.05, 0.00, 0.00, 0.00, 0.00, 0.00, 0.00, 0.00, 0.00, 0.00, 0.00, 0.00, 0.00, 0.00, 0.000, 0.00, 0.000, 0.00, 0.000, 0.00, 0.000, 0.00, 0.00, 0.00, 0.00]

      lambda_sterics:        [1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 1.00, 0.95, 0.90, 0.80, 0.75, 0.70, 0.65, 0.60, 0.55, 0.50, 0.45, 0.40, 0.35, 0.325, 0.30, 0.275, 0.25, 0.225, 0.20, 0.175, 0.15, 0.10, 0.05, 0.00]

As you may notice, there is an error in lambda state 46 of the complex phase. The defined values are:

[lambda_restraints,lambda_electrostatics, lambda_sterics] = [0.0, 1.0, 0.3]

However, this state should have been:

[1.0, 1.0, 0.3]

This incorrect definition appears to cause convergence issues in the free energy analysis. I am therefore wondering:

• Is it possible to skip or remove a single lambda state during post-processing?
• Alternatively, is there a recommended way to reweight or correct this without re-running the entire calculation?

If anyone has encountered a similar issue or has suggestions on how best to proceed, I would greatly appreciate your advice.

Thank you very much for your help.

[mikemhenry]

@MartinFuentetaja This is a good question, I am not sure the best way to skip/remove a lambda state during post processing.

@ijpulidos Might have an idea.