diff --git a/README.md b/README.md index 30662cca..41359895 100644 --- a/README.md +++ b/README.md @@ -18,20 +18,20 @@ Specifically, if you want to receive updates if we uncover any problems, it is i ## Challenge Overview (This is reproduced from the [SAMPL6 Website](https://drugdesigndata.org/about/sampl6)) -SAMPL6 includes challenges based on aqueous host-guest binding data (binding free energies and, optionally, binding enthalpies) for three different host molecules, and on physical properties (specifically, distribution coefficients and possibly solubilities), for a set of fragment-like molecules. -Host-guest systems test simulation methods, force fields, and solvent models, in the context of binding, without posing the setup issues and computational burden of protein simulations. -The physical properties offer efficient tests of force field accuracy when detailed simulations are used, and can also be used to test continuum solvation models and knowledge-based prediction methods. +SAMPL6 includes challenges based on aqueous host-guest binding data (binding free energies and, optionally, binding enthalpies) for three different host molecules; and on physical properties (distribution coefficients and possibly solubilities), for a set of fragment-like molecules. +The host-guest systems are useful to test simulation methods, force fields, and solvent models, in the context of binding, without posing the setup issues and computational burden of protein simulations. +The physical properties offer efficient tests of force field accuracy when detailed simulations are used, and can also test pKa prediction methods, continuum solvation models, and knowledge-based prediction methods. +SAMPL6 will also introduce a new challenge component, the “SAMPLing challenge”, in which computational methods will be evaluated on how efficiently their calculations approach well-converged reference results generated by the organizers. +Participants will be provided with machine readable setup files for the molecular systems, including force field setups, along with recommended cutoffs and treatments of long-ranged interactions. +The SAMPLing challenge is expected to include one or more cases from each challenge component (host-guest binding on each system; log D calculation). -Machine-readable structure files for the hosts, guests, and physical property solutes will be provided when each challenge component opens. -Note that the physical property component of SAMPL6 is expected to have a later opening date than the host-guest part, because the measurements are being done on a later schedule. +**As of August 24, all of the information and data files needed to start on the host-guest component, including machine-readable structure files for the hosts and guests are posted, so this challenge is open! +Files are hosted at github.com/mobleylab/SAMPL6.** +We estimate that the physical property and SAMPling parts of SAMPL6 will open in October 15, 2017 and September 20, 2017, respectively. +Status updates will be posted here and announced by email to the D3R SAMPL list and on the D3R Twitter account; we also encourage participants to “watch” the GitHub repository for notifications of file changes/availability and relevant discussions. -SAMPL6, will also introduce a new challenge component, the ``SAMPLing challenge'', where participants will be provided with input files for prepared systems that the organizers will be simulating, and evaluated on how efficiently their calculations; i.e., with the least simulation time and/or energy calls, to within a specified tolerance of the organizers’ well-converged “gold standard” answers for the provided systems, using cutoffs and long-range treatments recommended by the organizers. -Participants will still be responsible for preparing the provided systems for use with their chosen free energy method, but provided files will include fully solvated systems including all force field parameters and other details. - -We thank Drs. Bruce Gibb (Tulane U.) and Lyle Isaacs (U. Maryland) for providing the host-guest data, and John Chodera, Mehtap Isik, and Merck for the distribution coefficient data. - -Further information on the host-guest and physical property components of SAMPL6 follow. -Tentatively, the host-guest components of the challenge opens Aug. 23 with submissions due Jan. 12. +Further information on both the host-guest and physical property components of SAMPL6 follow. +Thanks to Drs. Bruce Gibb (Tulane U.) and Lyle Isaacs (U. Maryland) for providing the host-guest data, and Dr. John Chodera, Mehtap Isik, and Merck for the distribution coefficient data. ### Gibb Deep Cavity Cavitand (Octa Acids) binding of guests @@ -51,26 +51,21 @@ Data will be provided for ~14 guests, including several FDA approved drugs. Background information on CB8 may be found in a number of publications, including DOI 10.1021/jp2110067, 10.1002/chem.201403405, and 10.1021/ja055013x. ### Physical properties -The SAMPL6 physical property challenge will center on predicting physicochemical properties for 25-50 fragment- and drug-like small molecules that small molecule protein kinase inhibitors (or fragments thereof). +The SAMPL6 physical property challenge will center on predicting physicochemical properties for 25-50 fragment- and drug-like small molecules that small molecule protein kinase inhibitors (or fragments thereof). Because the SAMPL5 logD challenge highlighted the difficulty in correctly predicting transfer free energies involving protonation states, we will provide participants with experimental pKa values for these compounds. We will ask participants to predict distribution coefficients (logD) at a single pH and (as a separate challenge), provided the measurements can be completed in time, pH-dependent solubilities for these compounds. -The experimental data being measured include: - -- pKa values, measured by electrochemical and/or UV-metric titration -- pH-dependent distribution coefficients (logD) of one or both of the following types: - - water and cyclohexane (as in SAMPL5) - - water and octanol (new in SAMPL6) -- pH-dependent solubility measurements performed using CheqSol (tentatively) +The experimental data being measured include pKa values, measured by electrochemical and/or UV-metric titration; and pH-dependent distribution coefficients (logD) of one or both of the following types: +- water and cyclohexane (as in SAMPL5) +- water and octanol (new in SAMPL6) -These measurements will be performed on Sirius T3 instruments from Sirius Analytical at Merck’s Rahway site. +There is also a possibility that solubilities will be measured, using the CheqSol method. All of these measurements will be performed on Sirius T3 instruments from Sirius Analytical at Merck’s Rahway site. The exact size of the dataset will depend on practical data collection throughput. An initial batch of ~25 fragment-like compounds is currently being assayed, with the prospect for additional measurements performed subsequently. Post-challenge follow-up experiments are possible and will be conducted as needed. +We hope to provide a preliminary list of compounds by September 15 to allow participants to begin planning. The final challenge will include logD and, if available, solubility prediction. + Distribution coefficients were included in the SAMPL5 challenge (overview doi:10.1007/s10822-016-9954-8 and experiment doi:10.1007/s10822-016-9971-7; JCAMD special issue https://link.springer.com/journal/10822/30/11/page/1); in many cases, they were predicted as if they were partition coefficients, using solvation free energies in the relevant solvents. The difference between distribution coefficients (logD, which reflects the transfer free energy at a given pH including the effects of accessing all equilibrium protonation states of the solute in each phase) and partition coefficients (logP, which reflects the free energy of transfer for the neutral form only) proved particularly important. In some cases, other effects like the presence of small amount of water in cyclohexane may also have played a role. - -Tentatively, this portion of the challenge will begin October 15 and close January 15; this page will be updated as additional details become clear. -We hope to provide a preliminary list of compounds by September 15 to allow participants to begin planning.