Two types of projects can be found in R.E.DD.B.:
-1.1- A "Whole molecule" project, which corresponds to an intact (un-broken) molecule. Examples are small organic or inorganic molecules such as solvent (DMSO, ethanol, cyclohexane etc...), and ligands of proteins or nucleic acids.
-1.2- A "Molecule fragment" project, which corresponds to a part (or fragment) of an organic or inorganic macro-molecule. This means that some atoms have to be removed from the structure(s) used in the charge derivation procedure to obtain the target fragment. Examples are amino acid (AA) fragments 'NH-CH(R)-CO' where the atom charge values are generally derived using capped amino acids 'ACE-AA-NME', nucleotide fragments originating from the fusion between dimethylphosphate and the corresponding nucleosides, or monosaccharide fragments. These fragments are generally compatible with previously existing ones (available in force field topology databases), and used to construct macro-molecules such as proteins, nucleic acids or polysaccharides.
Van der Waals, dihedral and electrostatic interactions are the three major components of a force field for an accurate representation of molecular conformations and inter-molecular interactions.
To correctly describe electrostatic interactions, it is crucial to rigorously define the atom charge values for the studied molecule(s) in order to produce trustful molecular dynamics or docking simulations.
RESP and ESP charge values can be obtained using various methods, algorithms and programs. Charge values are highly dependent on [(i) quantum mechanics programs, theory level/basis set and molecular conformation used in geometry optimization and molecular electrostatic potential calculations, (ii) surface or grid algorithms, molecular conformation and orientation used in molecular electrostatic potential computation, (iii) different fitting approaches and (iv) human errors]. Moreover, the corresponding charge derivation procedures are often tedious, time-consuming and error-prone. Consequently, many charge values published in the literature are of poor quality, not reproducible, and some of them are even totally wrong!
-2.1- To obtain highly reproducible RESP or ESP charges, the computational details about the charge derivation procedure have to be known. Thus, many computational details are requested during a R.E.DD.B. submission. In particular, since RESP and ESP charges are affected by molecular conformation and orientation (see the Bibliography section), the latters have to be fully characterized. To solve the orientational dependence of RESP and ESP charges, multi-orientation RESP or ESP fit has been implemented in the R.E.D. program, and for the first time allows the user to derive highly reproductible RESP or ESP charges independently of the quantum mechanics program or initial structure used in the approach.
-2.2- To obtain RESP or ESP charges of high quality, several conformations for a molecule are used in the charge derivation process. Hence, this approach has been named multi-conformation RESP or ESP charge derivation. The resulting charge values are more general, and suitable for molecular dynamics and docking studies (see the Bibliography section).
-2.3- More complex procedures involve different molecules in the charge derivation procedure. In this case, the procedure has been named multi-molecule RESP or ESP charge derivation. The resulting atom charge values for the target molecules (or fragments) are more general but also compatible with pre-existing values belonging to other molecules (or fragments) (see the Bibliography section).
It is strongly recommended to submit projects involving multiple molecules, multiple conformations and/or multiple orientations instead of basic and limited projects based on a single molecule, a single conformation and single molecular orientation. The R.E.D. program has been developed with a unique objective in mind: deriving RESP or ESP charges of high reproducibility and high quality. R.E.D. also simplifies submissions in R.E.DD.B. since the files required during the upload phase are automatically generated by this program (versions II and III). Thus, it is strongly advised to use R.E.D. to generate the data corresponding to the project which is going to be submitted to R.E.DD.B.
A R.E.DD.B. code is automatically attributed to a R.E.DD.B. project once it has been sucessfully uploaded in R.E.DD.B. This code should be used by its author(s) to reference a R.E.DD.B. project in the corresponding publication. Thus, it might be more suitable to submit a project to R.E.DD.B. before its publication. Such an approach allows the author of a project to incorporate the R.E.DD.B. code(s) in the manuscript before sending it to the journal editor. In these conditions, the R.E.DD.B. code(s) also help(s) the journal reviewers to study the data described in the manuscript. Consequently, the goal of a R.E.DD.B. code is to provide a rigorous link between the RESP or ESP derived charge values and the corresponding publication ensuring the reproducibility of the published results.
Two types of project code are generated depending on the type of project submitted to R.E.DD.B.: 'W-$i' or 'F-$j' ($i and $j being the total number of "Whole molecule" or "Molecule fragment" projects available in R.E.DD.B. at the time the user submits her/his project, respectively).
A R.E.DD.B. project can be temporary protected or hidden to the scientific community. The choice of protecting a project and the period of protection is made by its author during the project submission procedure in R.E.DD.B.
This feature has been implemented in R.E.DD.B. to allow the author of a R.E.DD.B. project to protect her/his data for a period of 3, 6 or 12 months (for instance before publication). Then, after this period of protection and in agreement with its author(s), the project is deprotected and the data are fully available to the scientific community.
If the author of a R.E.DD.B. project decides to protect her/his project, the IP address of the machine used to perform the submission is automatically recorded by the R.E.DD.B. server. Once the project is uploaded, the author can only access her/his project by using the IP used during the project submission, and the correct path to the project directory (i. e. REDDB-url/projects/'REDDB-code'/). The author can only download the corresponding data by using the correct path to the compressed archive (i. e. REDDB-url/projects/'REDDB-code'/'REDDB-code'.tar.bz2). In fact, the computer IP address is used to identify the machine which is authorized to access the data. Thus, during the period of protection of a R.E.DD.B. project, only the author of the project and the R.E.DD.B. administrator have access to the protected data.
Three steps have to be followed to submit a project to R.E.DD.B.:
-5.1- First, the author has to register in the R.E.DD.B. web site, and submit her/his project to R.E.DD.B. (see FAQ -7- concerning the information required for a project submission).
-5.2- The project submitted is not directly displayed on a R.E.DD.B. web page. Once the submission is completed and validated, a temporary URL address is generated and automatically sent by email to the author. Then, this project will go through a "peer review" system to study the project. Researchers working in the field of computational chemistry and force field development throughout the world have agreed to participate in the evaluation of the projects submitted to R.E.DD.B.
-5.3- After a few weeks, the referee reviews and comments are sent to the project author, who will have modify her/his data accordingly. If necessary, the author will have to re-submit her/his new data to R.E.DD.B. This new set of data is checked and made available in R.E.DD.B. by the admistrator if in agreement with the reviewer suggestions.
Before submitting her/his project to R.E.DD.B., an author can download the documentation available here to study what is requested for a project to be accepted in R.E.DD.B. The referee of a project submitted to R.E.DD.B. can also download this documentation to help her/him to establish a review.
Two scripts have been written to help users to submit their data to R.E.DD.B. The first script allows creating a configuration file compatible with the data generated by the R.E.D. program. The second script is used to select the data to be submitted in R.E.DD.B. based on the information available in this configuration file. The README.txt file available within the Script-REDDB.tgz archive file provides information about the procedure the user has to follow.
RESP and ESP charge derivation involving several different molecules, conformations and/or molecular orientations is a complex task. The R.E.D. program (versions II and III) has been designed for this purpose. Please read the latest R.E.D. Manual and the R.E.D. Frequently Asked Questions besides the R.E.DD.B. FAQ.
The R.E.DD.B.2t (Bis & test) web site has been designed to track bugs in the system. It can also be used by anybody interested in learning how to submit new projects to the official RESP ESP charge DDataBase. Thus, this "Bis & test" web site is useful to know the information required for an official R.E.DD.B. submisssion, and can be used to perform blind tests. However, be aware that, althought R.E.DD.B.2t works as R.E.DD.B., the projects and registered users contained in this R.E.DD.B.2t site are regularly erased without warning. Indeed, the "Bis & test" web site has not been designed to handle official data.
Download and study pre-existing R.E.DD.B. projects. Many complex projects are already available in R.E.DD.B.
A general public help is now provided with the q4md-forcefieldtools mailing list. Any researcher can participate in this mailing list by answering and/or sending queries at firstname.lastname@example.org after registration at email@example.com. To register in the q4md-fft mailing list just send an email to firstname.lastname@example.org with "subscribe q4md-fft" in the email subject or body (to un-subscribe just send "unsubscribe q4md-fft"). Archives of the q4md-fft mailing list are public.
We are also registered in the AMBER and CCL mailing lists, and we will answer to the queries about the q4md force field tools in these two mailing lists as well.
Finally, a tutorial describing R.E.DD.B. is now available.
-7.1- First, one has to provide all the computational conditions regarding the charge derivation procedure used for the R.E.DD.B. project reported. Based on these information, a "Summary of information" (corresponding to an 'index.php' file) is generated.
a) This involves details about (i) the geometry optimization step [quantum mechanics program, basis set, theory level and specific keyword(s) used], (ii) the Molecular Electrostatic Potential computation step [quantum mechanics program, basis set, theory level used, surface or grid algorithm and specific keyword(s) used] and (iii) the fitting step (program used, and number of stage(s) in the fit).
b) This also involves information about the number of molecule(s) (with their corresponding IUPAC name and keywords), the number of conformation(s) for each molecule, and the number of molecular orientation(s) (with the corresponding re-orientation procedure) for each conformation used in the charge derivation process.
-7.2- Then, one has to provide three different types of files in a R.E.DD.B. project submission i. e. (i) Tripos mol2 file(s), (ii) PDB file(s) (see also information in Wikipedia) and (iii) input(s) for the fitting program used in the charge derivation procedure [AMBER force fields use the RESP program, while the lastest CHARMM force fields use the Fitcharge program. The input(s) for the Pdm97 program can be uploaded in R.E.DD.B. as well].
a) Cartesian coordinates (optimized by quantum mechanics) of each of the whole molecules used in the RESP or ESP charge derivation procedure with the information regarding the molecular orientation(s) and molecular conformation(s) have to be provided in the PDB format. A PDB file is required for every molecules, the Cartesian coordinates of each conformation being seperated by the 'TER' keyword, and the information regarding the molecular orientation selected being added in the PDB file header as a REMARK. Click here to display an example of molecule (cyclohexane) where two conformations (chair and twist-boat) and four different molecular orientations (REMARK REORIENT ...) for each conformation were used in the charge derivation procedure.
b) The Tripos mol2 file format is powerful since many pieces of information characterizing the structure studied are present in this format (i. e. the Cartesian coordinates, atom names, atom connectivities, atom charge values and force field atom types). This is THE format used in R.E.DD.B. to store RESP or ESP atom charge values and topology information. The number of Tripos file(s) to be uploaded is set by the author of the R.E.DD.B. project, and is highly related to the number of molecule(s) used in the RESP or ESP charge derivation procedure. Click here to display several examples (see also the Bibliography section). In every cases, the number of Tripos files uploaded is independent of the number of molecular orientations and conformations used in the RESP or ESP charge derivation process.
c) One has to provide the input(s) of the fitting program used in the charge derivation procedure [i. e. RESP, Fitcharge or Pdm97 input(s), so far]. Indeed, the fitting step is crucial in the charge derivation process of a molecule. Many different options concerning the choices of the charge equivalencing approach and the presence/value of restraints during the fit (among many others) can be chosen by the author(s). Thus, requesting the input(s) of the fitting program in a R.E.DD.B. project submission is the only way to ensure the reproducibility of the charges reported...
-7.3- Although R.E.DD.B. is not devoted to store force field related information such as force field atom types or new force field parameters, the author of a R.E.DD.B. project can nevertheless provide such files (or scripts) compatible with the charge derivation procedure reported. Additional files that can be uploaded are the following:
a) A script to convert Tripos mol2 file(s) (force field atom type independent) into AMBER LEaP OFF library(ies) (force field specific),
b) A script to convert Tripos mol2 file(s) into CHARMM RTF or PSF library(ies) (force field specific),
c) A file which provides new force field parameters [compatible with the Tripos mol2 file(s)],
d) A file (free format) the author wishes to upload to better describe the corresponding R.E.DD.B. project (any type of information),
e) A second file (free format) the author wishes to provide (a .jpg image for instance).
-7.4- Remarks and consequences
a) All these requirements may be tedious and complicated after a first try, but by requesting these computational details the quality and reproducibility of the RESP or ESP charge reported are ensured.
b) It is strongly advised to search/download pre-existing R.E.DD.B. projects before submitting a project to R.E.DD.B. for the first time.
c) During a R.E.DD.B. submission, the user is guided by many available definitions within "popup" windows and Internet sites.
d) All the files required for a R.E.DD.B. submission are automatically generated by the R.E.D. program (versions II and III). Although, the execution of R.E.D. is not required, it makes a R.E.DD.B. submission easier.
e) Several structures with corresponding Tripos/PDB files have to be considered as a single R.E.DD.B. project if all these structures were used together in a single charge derivation procedure.
f) Similar or redundant projects might be found in R.E.DD.B. involving the same structure(s). These projects might only differ by some computational details (same conformation(s), same computational details but different molecular orientation(s) or same molecular orientation(s) and conformation(s) but different basis set used in the MEP computation, for instance). These potential 'redundances' will authorize rigorous comparisons between different charge derivation procedures.
Five differences distinguish the use of the PDB and Tripos file formats in a R.E.DD.B. project:
-8.1.-- The Tripos file contains information about atom connectivities for both "Whole molecule" and "Molecule fragment" projects (while the PDB format does not contain any atom connectivity information).
-8.2.- The Tripos file does not contain any information about the molecular conformation(s) and orientation(s) used in the charge derivation process (this information is stored in the PDB files for both "Whole molecule" and "Molecule fragment" projects).
-8.3.- The Tripos file contains the atom charge values originating from the charge derivation procedure for both "Whole molecule" and "Molecule fragment" projects (while the PDB format does not contain any charge values).
-8.4.- The Tripos file might contain force field atom type information for both "Whole molecule" and "Molecule fragment" projects (while the PDB format does not contain any force field related information).
-8.5.- And the most important, the Tripos file contains a fragment of molecule if a "Molecule fragment" project is obtained, while the PDB format always contains _all_ the atoms of the molecules used in the charge derivation procedure independently of the project type submitted to R.E.DD.B.
PDB files and Tripos files, input(s) of the fitting program used in the charge derivation, and a "Summary of information" are always available in a R.E.DD.B. project. These files can be used for research, but also for educational purposes.
-9.1.- A "Summary of information" describing the computational conditions used in the charge derivation procedure is available in each R.E.DD.B. project. It is based on the information provided by the author during the corresponding project submission procedure, and can be accessed via the following URL REDDB-url/projects/'REDDB-code'/.
-9.2.- The "PDB file(s)" available in a R.E.DD.B. project describe the molecules [molecular conformation(s) and orientation(s)] used in the charge derivation procedure. The Cartesian coordinates in PDB files are always those belonging to 'whole/intact' molecules (i. e. no molecule fragment is represented in the PDB format in R.E.DD.B.) and correspond to geometries optimized by quantum mechanics. Thus, PDB file(s) might be used to reproduce the reported charge values as they represent a good starting point to the time-consuming geometry optimization step (if the optimization step has to be redone; to increase the accuracy of the Cartesian coordinates of each PDB structure the R.E.D. program generates PDB files with four digits after the decimal point). PDB files might also be used to visualize the structure(s) and the molecular conformation(s) and orientation(s) in graphical interfaces. Consequently, R.E.DD.B. can also be seen as a database of small molecules optimized by quantum mechanics.
-9.3.- The "Tripos mol2 file format" is used to describe the derived RESP or ESP charges, and the molecular topology information of the target molecule or molecular fragment. Thus, it can be considered as a force field library precursor. This is the file which has to be loaded in a molecular dynamics or docking program to perform the molecular modeling study. Two main cases can be differentiated:
a) If the Tripos file format is recognized by the molecular dynamics or docking program it can be directly used (after having incorporated some force field atom type definitions). Nowadays, the tendency in all molecular modeling programs is to be compatible with many file formats, and many programs and graphic interfaces automatically recognize the Tripos file format.
b) If the Tripos file format is not directly recognized by the molecular dynamics or docking program, it has to be considered as a precursor of some internal format or libraries. For instance, since the AMBER8 version this file format is now recognized by LEaP and can be easily converted into the corresponding AMBER OFF library with the adequate script. The Tripos file format can also be converted into RTF or PSF CHARMM file format.
In many molecular dynamics software (AMBER, CHARMM, Tinker, or Gromacs among many others), an internal format or library is defined with a particular molecular topology (i. e. the atom connectivities, the atom and residue names, the atom charge values and the force field atom types are rigorously defined while the Cartesian coordinates remain free). Consequently, the internal library will be compatible with any considered molecular structure [i. e. no distinction between orientations, conformations, or even chirality (enantiomers and diastereisomers are not differenciated)]. In the hypothesis of using a Tripos file as a precursor of such an internal library, only the topology information available in the Tripos file is required, and the Cartesian coordinates do not really matter. This Tripos file can be theoretically compatible with any set of Cartesian coordinates belonging to the system under study.
-9.4.- Since the fitting step is crucial and many different choices can be done by the author(s), the "input(s) of the program used in the charge fitting approach" is(are) required in a R.E.DD.B. submission. Their purposes are multiple: (i) help to reproduce the atom charge values reported in R.E.DD.B., (ii) detect potential human errors performed by the author, and (iii) provide examples or tutorials for novice users.
-9.5.- R.E.DD.B. gives the opportunity to the author of a R.E.DD.B. project to upload five "force field related files": scripts for the automatic conversion of Tripos mol2 files into AMBER OFF and CHARMM RTF or PSF libraries, new force field parameters, and more generally any type of force field related information.
-9.6- Links to Wikipedia (the Free Encyclopedia)
Finally, for each project and molecule name provided in R.E.DD.B. an Internet link to Wikipedia is automatically generated. Such links are useful as they provide general information about the molecules and projects available in R.E.DD.B. Two cases are possible: Either a matching article is found in Wikipedia, or no article is available and the R.E.DD.B. user could then initiate the writing of a new article in Wikipedia about the molecules/project described in R.E.DD.B.
First, no registration is required to perform a search or to download R.E.DD.B. projects. The search and the download of R.E.DD.B. projects is performed via the "Download projects" tool. Five different search methods are available in R.E.DD.B.: "project code" (if it is known), "molecule keyword", "molecule name", "author lastname" and by "theory level/basis set" [the searches being independent of the character case (upper or lower)]:
-10.1- The project code entered in the search tool must be the _exact_ project code available in R.E.DD.B.
-10.2- The author lastname typed in the search tool must also be the _exact_ author lastname available in R.E.DD.B. The searched author name corresponds to the single author registered in R.E.DD.B. (i. e. the R.E.DD.B. author name or user who submitted the project). Thus, all the authors of the project reported in R.E.DD.B. can be entered in the project "abstract" and in the corresponding publication reference.
-10.3- The molecule keyword or molecule name typed in the search tool does not need to be the exact molecule keyword or molecule name provided by the project author during the R.E.DD.B. submission. Indeed, it can be _shorter_ (but not longer), and still lead to a positive match.
-10.4- The theory level and/or basis set written in the search tool has to correspond to the exact theory level/basis set used in the MEP computation. The theory level and basis set can be used together or independently when performing a search in R.E.DD.B.
Finally, a new tool (Browser type), named "List projects", has been developed to quickly display the projects available in R.E.DD.B. (the projects are classified into "Whole molecule" and "Molecule fragment" projects).
The following browsers have been tested:
- Internet Explorer from Microsoft,
- Konqueror from KDE,
- Netscape (please, do not use the old Netscape 4.XX available on SGI/IRIX 6.5 !),
- Safari was not tested. We would be interested in getting any feedback about Safari.
Extensive tests have been carried out using Mozilla/Firefox, Opera and Internet Explorer. Consequently, it is strongly recommended to use one of these browsers...
First, a R.E.DD.B. project can be updated by its author after it has been involved in the "peer" review system and after the project has been officially accepted in R.E.DD.B. (see FAQ n°5 for more information). Two types of information can be added by using the "Update project" tool:
- The publication reference corresponding to a R.E.DD.B. project can be provided at any time once it is known. Consequently, it might be more suitable to submit a project to R.E.DD.B. before publication (see FAQ -3- for more information).
- The five force field related files can be added to a project at any time (see FAQ -7- for more information).
It is possible to update a project more than once. However, only information which was not provided during the project submission procedure or during a first update might be provided during a second update. The date of the last update for a R.E.DD.B. project is recorded in the database, and added in the project "Summary of information" (see FAQ -7- for more information).
Second, new tools have also been developed to correct and delete projects recorded in R.E.DD.B. Only, the R.E.DD.B. administrator has the rights to perform these operations. Please, contact us if you wish that we correct or remove one of your projects.
The R.E.DD.B.2t (Bis & test) web site has been designed to learn how to submit a project and to perform blind tests before submitting an official project to R.E.DD.B.
If you find a bug in the R.E.DD.B. web site, please send us an email describing the problem, the browser and operating system used. More generally, contact us if you find any mistake in a project, or for any suggestion or improvement.
A Golden book is now available. It allows R.E.DD.B. users to write messages, comments and suggestions about R.E.DD.B.
F.-Y. Dupradeau, C. Cezard, R. Lelong, E. Stanislawiak, J. Pecher, J.C. Delepine, & P. Cieplak, R.E.DD.B.: a database for RESP and ESP charge values and force field libraries, Nucl. Acids Res. (Database issue), 2008, D360-D367, [Abstract].