js3r3-FreeEnergyProtocol.txt

Name

Alchemical Free Energy Calculation

Software

Gromacs, PMX

Parameter

Assumed pH 7.0
10 ns Molecular Dynamics simulations at 300 K. Integrator : sd. Berendsen pressure coupling.
Morphing : Short 50 ps MD at 300 K on 200 extracted conformations from state A and state B simulations.
Morphing : sc-alpha = 0.5, sc-sigma = 0.25.
Morphing : Integrator : md. Pressure coupling : berendsen. Temperature coupling : velocity rescale

Method

The protein used for free energy calculation was taken from the structure QJAN. Ligands 3D coordinates were obtained by docking using Glide and SP protocol, with constraints applied on the common substructure with either CatS_15, CatS_20 or CatS_24. Alchemical free energies were calculated using Gromacs and OPLS-AA force field, some scripts from the PMX software and some in house developed scripts. Hybrid structures and topologies were built using a modified version of the MOL2FF package developed in our team. CatS_67 was used as reference structure for the free energy calculations. Equilibrium 10 ns MD simulations were performed for the two states (corresponding to lambda 0 and 1), using Gromacs and OPLS-AA force field. Snapshots from the equilibrium runs were extracted to spawn 100 simulations of 50 ps each to alchemically morph between the two states of the system. The work values over every non-equilibrium transition were extracted and further used to estimate the free energy differences relying on the Crooks Fluctuation Theorem and utilizing Crooks-Gaussian Intersection as estimator.

Answer 1

Yes

js3r3-PosePredictionProtocol.txt

Name

D3R-GC3-Pose-Redocking-Xray-FE-Score

Software

CACTVS Chemoinformatics Toolkit v3.433/Schrödinger Suite 2016-1/Glide/CORINA v3.60/UCSF Chimera v1.10.2

System Preparation Parameters

Protonation state of ligands at pH 7.0+/-1 was considered.

System Preparation Method

The protein 'qjan' from the complex with CatS_15 was used for docking. Protein was prepared (hydrogens added) using the Schrödinger Suite. 3D coordinates of the ligands (MOL2 format) with different protonation states corresponding to a pH of 7.0+/-1 were generated using Schrödinger LigPrep. Binding site was defined as a sphere with 20 Å radius around a virtual point with coordinates (-7,12,-8).

Pose Prediction Parameters

Glide software with the SP protocol and constraints on the common substructure with either CatS_15, CatS_20 or CatS_24.

Pose Prediction Method

Docking runs with ligands from the Free Energy Set 1 were executed using Glide software with the SP protocol, and default values, except the constraints applied on the common substructure with either CatS_15, CatS_20 or CatS_24. The poses with the best docking score (and with the conformations of groups that have no constraints similar with those of the other compounds from the FE dataset) were selected for free energy calculations (1 pose per compound). Protein structures were converted into PDB format for submission using UCSF Chimera, and the docking poses were converted into MOL format using CORINA (the MOL format corresponds to the SDF output format in CORINA).

Answer 1

Yes

Answer 2

No