Simulation of Diffusional Assosiation (SDA) offers solutions to a number of simulation tasks for biological macromolecules and can reproduce experimental results. However, it cannot be used by a wide audience because of its multitude of different parameters and options that are often interdependent. Setting these parameters correctly and understanding their function requires expert knowledge in Brownian dynamics simulation. In addition, the program relies in part on shell scripts which limits it to Linux computers. webSDA is a web server which aims to eliminate these obstacles and make SDA functionality available to a broader audience. webSDA could be used as a tool for teaching Brownian dynamics or for experimentalists dealing with molecular interactions. webSDA was designed to run simulations with small molecules and/or short simulation runs. To run a simulation for a time period longer than 24 hours, the standalone SDA has to be used. In this case, the web server can be used to prepare the input for SDA, which is one of the major difficulties in using standalone SDA.
For the computation of webSDA jobs, a cluster with 9 compute nodes with 48 cores on each node is used. The queuing system on the compute cluster uses the Terascale Open-source Resource and QUEue Manager (TORQUE) to manage submitted webSDA jobs. If the jobs exceed the current computational capacity, the jobs will be queued for the next available slot. For calculation of interaction grids, clustering, bootstrapping of association rate constants and generation of trajectories, 2 cores of one node are assigned to each job, whereas for SDA jobs, 8 cores of one node are assigned to each job. The maximum run-time of a job is 24 hours. For SDA jobs, output files are written and provided to users for the 24 hours that the job executed. For other types of job, no output files are generated if 24 hours are exceeded.
The force field model used in webSDA is described in the appendix of Martinez et al. (2015)
and its cited references, and on the SDA 7 website.
The force field contains adjustable parameters in the electrostatic and hydrophobic desolvation terms,
which webSDA sets to reasonable default values.
Electrostatic desolvation grids are calculated in zero salt conditions, regardless of the ionic strength used in solving the Poisson Boltzmann equation. This is done to allow the use of an ionic strength independent value of parameter α in the potential term (see Eqn. A4 in Martinez et al. (2015)), as described in Gabdoulline and Wade (2009). Prior to December 2015, webSDA used the ionic strength dependent approach described in Gabdoulline and Wade (2001). As electrostatic desolvation generally makes a small contribution to the overall interaction free energy between solutes, any differences due to this choice are assumed to be small.
The hydrophobic desolvation potential contains a parameter β that defines the proportionality between the hydrophobic desolvation energy difference that occurs when two solutes form a binding interface, and the total loss of solute surface area on binding. In webSDA a value of -0.013 kcal/mol·Å2 is used. This value has been chosen as it has been shown (Gabdoulline and Wade (2009)) to give a good balance between accuracy and computational efficiency in docking and association calculations. In multiple molecule simulations, a larger magnitude of up to -0.019 kcal/mol·Å2, may give a better agreement to experimental results.
Benchmarks for SDA have been computed (Martinez et al, submitted). webSDA supports
“SDA docking” and “SDA association” jobs with up to 20000 SDA runs and “SDA multiple molecules”
simulations of up to 120000 ps. If users want to run longer SDA jobs longer, they have
to download and use the standalone SDA 7.
For the examples given in webSDA, for “SDA docking” and “SDA association”, 200 SDA runs take less than one minute, 2000 SDA runs take ca. 2 minutes and 20000 SDA runs take ca. 20 minutes.
For the “SDA multiple molecules” example, a 2000 ps simulation takes ca. 1 minute and 20000 ps simulation takes ca. 3 minutes.
For interaction grid calculations, webSDA is able to process files that are up to the memory limit on the compute cluster (64 GB). As an example, the nucleosome (ca. 24000 atoms), it takes about 10 minutes to generate the grids.
webSDA uses the PDB2PQR software (version 2.0.0, http://www.poissonboltzmann.org/)
to convert PDB files to PQR files. In this step, all water
molecules in PDB files are deleted.
One limitation of this step is that, currently webSDA DOES NOT support the PDB2PQR conversion of ligands and cofactors. So if there are ligands or cofactors in PDB files and they are important for interactions of solutes, we strongly recommend users to generate their own PQR files with ligands or cofactors and upload these PQR files to webSDA.
First, check if you have the "NTR" or "CTR" problem below.
Check if all the records of the non-protein residues (ligands and waters (HOH or WAT)) have been changed "ATOM" to "HETATM", please delete all the waters that are not needed.
If there are other problems, please do not hesitate to contact us.
First, make sure that the chain ids are present and correct.
Delete the "CTR" and "NTR" specification from the pqr file (should not be needed anymore).If you test with a pqr file generated with WHATIF, please let us know the results.
The python script will try to add effective charge sites for
this residue/ligand if its net charge is different from 0.
Some empirical rules are applied:
The diffusion coefficients are computed with the dcc
(beta version...link not updated) tool provided in SDA 7. It is
a fast and simple algorithm (which still need to evaluated). In
order to use reliable input, we advise the use of the HYDROPRO
The correct information is needed in the case of:
Distance (Å) = (MaxDim1 + MaxDim2)/2 + 12. MaxDim1 is the maximal value of the x, y and z dimensions of the static solute and MaxDim2 is that of the mobile solute.
Make sure that the provided pdb files represents a correct bound structure: no overlap between the solutes and a minimum of 3-4 donor-acceptor pairs (hydrogen bonds).
First, two distances for the two solutes are computed: