From groot@organon.akzonobel.nl Wed Jan 4 03:33:41 1995 Received: from apou01.akzonobel.nl for groot@organon.akzonobel.nl by www.ccl.net (8.6.9/930601.1506) id DAA23486; Wed, 4 Jan 1995 03:26:59 -0500 Received: by apou01.akzonobel.nl (5.65/AKZO-WvdL/941013) id AA11239; Wed, 4 Jan 1995 09:28:36 GMT Received: by poppy.oss.akzonobel.nl (931110.SGI/930416.SGI) for @apou01.akzonobel.nl:chemistry@oscsunb.ccl.net id AA18219; Wed, 4 Jan 95 09:27:02 GMT Date: Wed, 4 Jan 95 09:27:02 GMT From: p.grootenhuis@organon.akzonobel.nl (Peter Grootenhuis) Message-Id: <9501040927.AA18219@poppy.oss.akzonobel.nl> To: chemistry@oscsunb.ccl.net Subject: SUMMARY disulfide bonds Cc: groot@poppy.oss.akzonobel.nl Reply-To: p.grootenhuis@organon.akzonobel.nl My question was: Netters, i want to design some additional disulfide bonds in a protein structure and i am wondering whether there is software that will help you to locate optimal positions for the corresponding point mutations. The answers (in order of arrival): ------------------------------------------------------------------------------- 1) Leif Norskov, Novo Nordisk A/S, Copenhagen, Denmark, lnl@novo.dk ... Your fellow countryman Dijke Baukstra developed a program some years ago to do exactly that. I don't have it, but I may be able to dig up a reference if you cannot ask him directly. ... [After contacting Prof Bauke Dijkstra, bauke@rugch2.chem.rug.nl, I obtained a copy of his program.] ------------------------------------------------------------------------------- 2) J. Bruce Pitner, Molecular Biology Department, Becton Dickinson Research Center, Research Triangle Park, NC 27709, pitner@bdrc.bd.com You might take a look at: 1. Pabo and Suchanek, Biochemistry, vol. 25, pp. 5987-5991 (1986) 2. Glockshuber, et al, Biochemistry, vol. 29, pp. 1362-1367 (1990) The second paper describes stabilization of an antibody Fv fragment by site-directed mutagenesis incorporating inter-chain disulfide bonds. They used a database of protein disulfide bond geometries created by the first paper's method. We've used a similar approach to stabilizing single chain antibodies but with an even simpler model. We compared the distances between the respective alpha and beta carbons of each pair of residues against a database of disulfides in similar environments. This gave a pretty short list of potential sites for linking the two separate chains, once you throw out pairs too close to the binding site. ------------------------------------------------------------------------------- 3) David Mosenkis, Tripos, david@tripos.com P. Balaram's group in Bangalore, India developed a program called MODIP to select appropriate sites for engineering disulfide bonds into protein structures. Their method is described in Protein Engineering vol.3, no.2, pp. 95-103, 1989. You can reach one of the authors, N. Srinivasan, at UBCG91S@CCS.BBK.AC.UK. ------------------------------------------------------------------------------- 4) Steve Muskal, STEVEM@mdli.com We used neural network models to predict a cysteine's disulfide bonding state given its local sequence context. The prediction accuracy was quite good. Ref: Muskal, S., Holbrook, S., Kim, S.H. Protein Eng. 3, 667-72 (1990) ------------------------------------------------------------------------------- 5) N.Srinivasan, UBCG91S@CCS.BBK.AC.UK The program MODIP selects sites in a protein of known 3D structure, wherein if Cys residues are introduced, a potential unstrained disulphide can be formed. Fuller details are available in: R.Sowdhamini, N.Srinivasan, B.Shoichet, D.V.Santi, C.Ramakrishnan and P.Balaram (1989) Prot. Engng. 3, 95-103. We have a version running in Silicon Graphics machine with f77 compiler (although it is not a graphics program). The object code can be distributed to any academic institution free of charge with the understanding that the program will not be used for any commercial purpose. We would like to have this agreement, because this program is likely to be commercialised with Tripos Inc. If you are interested in getting MODIP, please send me or Dr.Sowdhamini (both currently at Birkbeck college, London) a high density tape cartridge (DC 6150 - 150 Mbytes). We would then send you the program along with help files for installation and running the program. DIP contact in London: Dr.R.Sowdhamini or Dr.N.Srinivasan ICRF unit Department of Crystallography Birkbeck College Malet Street London WC1E 7HX U.K. ------------------------------------------------------------------------------- 6) Johan Postma,EMBL,Heidelberg,FRG,POSTMA@EMBL-Heidelberg.DE ... We have an efficient data-access mechanism for PDB data files. Recently I performed an analysis that may answer your questions. Distribution of CA-CA/CB-C (and CA-CA/CHI3; CB-CB/CHI3) from SS-bonded cysteins. The distribution of CACA-CBCB suggests that the "best" SS-bonds are observed when CACA(3.9)-CBCB(5.2);CACA(3.8)-CBCB(5.8); CACA(3.7)-CBCB(6.2) .... (translated by PG) ------------------------------------------------------------------------------- 7) Andy King, aking@dreamon.oxmol.co.uk It sounds like Cameleon would be ideal for your application. Cameleon provides an interactive graphical bridge between the sequence of a protein and its 3-dimensional structure. Cameleon allows users to work with multiple representations of the proteins, including a variety of property profiles, secondary structure predictions, alignments and homologous structures. Clicking on a residue in one display highlights that residue in all the other displays allowing easy tracking of regions of interest across all representations Cameleon is an ideal guide for the location of optimal sites for a variety of modelling operations, including additional disulphide bridge insertion, an example of which is actually included in the manual..... Let me know if you are interested or if you need more information about Cameleon before making a decision. ------------------------------------------------------------------------------- 8) Carlos Faerman, carlos@extreme.bio.cornell.edu There may be a specific program to do this but the simples idea you can try is: 1) to write a program that will explore either Calpha-Calpha distances or Cbeta-Cbeta distances and get a general idea about the residues that are at least somewhat close to each other. This preliminary test which you may have already done will give some useful hints. The major disadvantage is that you are not taking into account possible conformational changes... Anyhow this is what we attempted before actually preparing a XCYS X'CYS double mutant.... ------------------------------------------------------------------------------- Thanks a lot for your responses ! -------------------------------------------------------------------------------- Dr. Peter D.J. Grootenhuis --- CMC dept. RK2330 --- N.V. Organon P.O. Box 20 --- 5340 BH Oss --- The Netherlands Phone: 31-4120-61920 --- Fax: 31-4120-62539 E-mail: p.grootenhuis@organon.akzonobel.nl -------------------------------------------------------------------------------- From dimitris@3dp.com Fri Jan 6 09:45:12 1995 Received: from boris.3dp.com for dimitris@3dp.com by www.ccl.net (8.6.9/930601.1506) id JAA06442; Fri, 6 Jan 1995 09:45:07 -0500 Received: from europa.3dp.com by boris.3dp.com via SMTP (931110.SGI/930416.SGI) for chemistry@ccl.net id AA25372; Fri, 6 Jan 95 09:51:48 -0500 Received: by europa.3dp.com (931110.SGI) id AA03764; Fri, 6 Jan 95 10:04:11 -0500 From: "Dimitris Agrafiotis" Message-Id: <9501061004.ZM3762@europa.3dp.com> Date: Fri, 6 Jan 1995 10:04:10 -0500 X-Mailer: Z-Mail (3.1.0 22feb94 MediaMail) To: chemistry@ccl.net Subject: metrics for molecular diversity Content-Type: text/plain; charset=us-ascii Mime-Version: 1.0 I am looking for a review of all the metrics that have been used to measure molecular diversity in multidimensional physicochemical space. I am not so much interested in metrics of distance between two compounds such as Minkowski indices etc, but rather indices that measure the diversity exhibited by a particular set of chemical compounds. I would appreciate any pointers to books/reviews/papers on that subject and will summarize the results in a future note. Thanks for your help. -- Dimitris K. Agrafiotis, PhD | e-mail: dimitris@3dp.com 3-Dimensional Pharmaceuticals, Inc. | tel: (215) 222-8950 3700 Market Street | fax: (215) 222-8960 Philadelphia, PA 19104