TY - JOUR
T1 - Molecular surface complementarity at protein-protein interfaces
T2 - The critical role played by surface normals at well placed, sparse, points in docking
AU - Norel, Raquel
AU - Lin, Shuo L.
AU - Wolfson, Haim J.
AU - Nussinov, Ruth
N1 - Funding Information:
We thank Drs D. Covell, D. Fischer, R. Jernigan and J. V. Maizel for discussions. The research of R.N. been sponsored by the National Cancer Institute, DHHS, under contract no. 1-CO-74102 with Program Resources, Inc. The content of this publication do not necessarily reflect the views or policies of the DHHS, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The research of R.N. in Tel Aviv University has been supported in part by grant no. 91-00219 from the U.S. Israel Binational Science Foundation (BSF), Jerusalem, Israel. The research of H.J.W. and R.N. in Israel has been supported in part by a grant from the Israel Science Foundation administered by the Israel Academy of Sciences. R.N. acknowledges support by the Eshkol Fellowship. This work formed part of the PhD. Thesis of R. Norel, University of Tel Aviv. The graphics program used here is RasMol V 2.2, by Roger Sayle, Biocomputing Research Unit, University of Edinburgh.
PY - 1995/9/15
Y1 - 1995/9/15
N2 - Rigid-body docking of two molecules involves matching of their surfaces. A successful docking methodology considers two key issues: molecular surface representation, and matching. While approaches to the problem differ, they all employ certain surface geometric features. While surface normals are routinely created with molecular surfaces, their employment has surprisingly been almost completely overlooked. Here we show how the normals to the surface, at specific, well placed points, can play a critical role in molecular docking. If the points for which the normals are calculated represent faithfully and accurately the molecular surfaces, the normals can substantially ameliorate the efficiency of the docking in a number of ways. The normals can drastically reduce the combinatorial complexity of the receptor-ligand docking. Furthermore, they can serve as a powerful filter in screening for quality docked conformations. Below we show how deploying such a straight forward device, which is easy to calculate, large protein-protein molecules are docked with unparalleled short times and with a manageable number of potential solutions. Considering the facts that here we dock (1) two large protein molecules, including several large immunoglobulin-lysozyme complexes; (2) that we use the entire molecular surfaces, without a predefinition of the active sites, or of the epitopes, of neither the ligand nor the receptor; that (3) the docking is completely automated, without any labelling, or pre-specification, of the input structural database, and (4) with a single set of parameters, without any further tuning whatsoever, such results are highly desirable. This approach is specifically geared towards matching of the surfaces of large protein molecules and is not applicable to small molecule drugs.
AB - Rigid-body docking of two molecules involves matching of their surfaces. A successful docking methodology considers two key issues: molecular surface representation, and matching. While approaches to the problem differ, they all employ certain surface geometric features. While surface normals are routinely created with molecular surfaces, their employment has surprisingly been almost completely overlooked. Here we show how the normals to the surface, at specific, well placed points, can play a critical role in molecular docking. If the points for which the normals are calculated represent faithfully and accurately the molecular surfaces, the normals can substantially ameliorate the efficiency of the docking in a number of ways. The normals can drastically reduce the combinatorial complexity of the receptor-ligand docking. Furthermore, they can serve as a powerful filter in screening for quality docked conformations. Below we show how deploying such a straight forward device, which is easy to calculate, large protein-protein molecules are docked with unparalleled short times and with a manageable number of potential solutions. Considering the facts that here we dock (1) two large protein molecules, including several large immunoglobulin-lysozyme complexes; (2) that we use the entire molecular surfaces, without a predefinition of the active sites, or of the epitopes, of neither the ligand nor the receptor; that (3) the docking is completely automated, without any labelling, or pre-specification, of the input structural database, and (4) with a single set of parameters, without any further tuning whatsoever, such results are highly desirable. This approach is specifically geared towards matching of the surfaces of large protein molecules and is not applicable to small molecule drugs.
KW - Docking
KW - Molecular surface complementarity
KW - Protein-protein recognition
KW - Rigid-body matching
KW - Surface normals
UR - http://www.scopus.com/inward/record.url?scp=0029089732&partnerID=8YFLogxK
U2 - 10.1006/jmbi.1995.0493
DO - 10.1006/jmbi.1995.0493
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AN - SCOPUS:0029089732
SN - 0022-2836
VL - 252
SP - 263
EP - 273
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 2
ER -