High energy when applying restraint in one phase

[jbodosa]

Hello,

I am trying to use yank to get the absolute binding free energy of a charged ion to a charged small molecule. Below is the yaml input file and the last lines from the yank output- I want to modify the NBFIX between the ion and the oxygen on the molecule so I added them to the xml file as Exceptions since I read that the CustomNonbondedForce are not correctly read in yank.

I have two files, one with ion and molecule restrained and the the other with just the ion. I have noticed that whenever I apply the restraint I get huge energies in one state, not necessarily the one with the restraint. Can someone help with this issue?

Thank you
Jessica B

options:
  minimize: yes
  verbose: yes
  output_dir: explicit
  default_number_of_iterations: 500
  temperature: 298*kelvin
  pressure: 1*atmosphere
  checkpoint_interval: 10
  alchemical_pme_treatment: exact 
  resume_setup: no
  resume_simulation: no

solvents:
  water:
    nonbonded_method: PME
    nonbonded_cutoff: 12 * angstroms
    switch_distance: 10 * angstroms

systems:
  hydration-system:
    phase1_path: [ion_mol_wat_wnbfix.xml, ../ion_mol_ionwater.pdb]
    phase2_path: [ion_wat_wnbfix.xml, ../ion_ionwater.pdb]
    solvent1: water
    solvent2: water
    ligand_dsl: resname ion
    solvent_dsl: resname TIP3 or resname POT or resname CLA
    charmm_parameter_files: [../../forcefield/toppar_c36_jul20/top_all36_prot.rtf,
                             ../../forcefield/toppar_c36_jul20/par_all36m_prot.prm,
                             ../../forcefield/toppar_c36_jul20/top_all36_lipid.rtf,
                             ../../forcefield/toppar_c36_jul20/par_all36_lipid.prm,
                             ../../forcefield/toppar_c36_jul20/top_all36_carb.rtf,
                             ../../forcefield/toppar_c36_jul20/par_all36_carb.prm,
                             ../../forcefield/toppar_c36_jul20/top_all36_cgenff.rtf,
                             ../../forcefield/toppar_c36_jul20/par_all36_cgenff.prm,
                             ../../forcefield/toppar_c36_jul20/toppar_water_ions_charmm.str,
                             ../../forcefield/toppar_c36_jul20/stream/lipid/toppar_all36_lipid_model.str]

protocols:
  hydration-protocol:
    solvent1:
      alchemical_path:
        lambda_electrostatics: [1.0, 0.8, 0.6, 0.4, 0.2, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0]
        lambda_sterics:        [1.0, 1.0, 1.0, 1.0, 1.0, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.0]
    solvent2:
      alchemical_path:
        lambda_electrostatics: [1.0, 0.8, 0.6, 0.4, 0.2, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0, 0.0]
        lambda_sterics:        [1.0, 1.0, 1.0, 1.0, 1.0, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.0]


experiments:
  system: hydration-system
  protocol: hydration-protocol
  restraint:
    type: Harmonic
    restrained_receptor_atoms: resid 0 or resid 1 or resid 2 or resid 3 # atoms of mol
    restrained_ligand_atoms: resname ion # the ion
    spring_constant: 10.0 * kilocalories_per_mole/(angstrom**2)

WARNING: Did not converge to within specified tolerance.
max_delta = 2.075165e-05, tol = 1.000000e-12, maximum_iterations = 10000, iterations completed = 9999
A squared uncertainty is negative. Largest Magnitude = 0.000000
A squared uncertainty is negative. Largest Magnitude = 0.000000
Free energy of solvation: 42700.919 +- 224.027 kT (25286.923 +- 132.666 kcal/mol)
DeltaG solvent1         :   957.503 +- 223.317 kT
DeltaG standard state correction:             -1.540 kT
DeltaG solvent2         : 43656.882 +- 17.826 kT

Enthalpy of solvation   : 115199.749 +- 1690.088 kT (68219.779 +- 1000.848 kcal/mol)