Biomedical subjects

R Norel

Publications and source records attributed to R Norel.

5 recordsLinked to original sources

PubMed1995

Molecular surface complementarity at protein-protein interfaces: the critical role played by surface normals at well placed, sparse, points in docking.

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.

Computer Graphics↗

PubMed1994

Shape complementarity at protein-protein interfaces.

A matching algorithm using surface complementarity between receptor and ligand protein molecules is outlined. The molecular surfaces are represented by "critical points," describing holes and knobs. Holes (maxima of a shape function) are matched with knobs (minima). This simple and appealing surface representation has been previously described by Connolly [(1986) Biopolymers, Vol. 25, pp. 1229-1247]. However, attempts to implement this description in a docking scheme have been unsuccessful (e.g., Connolly, ibid.). In order to decrease the combinatorial complexity, and to make the execution time affordable, four critical hole/knob point matches were sought. This approach failed since some bound interfaces are relatively flat and do not possess four critical point matches. On the otherhand, matchings of fewer critical points require a very time-consuming, full conformational (grid) space search [Wang, (1991) Journal of Computational Chemistry, Vol. 12, pp. 746-750]. Here we show that despite the initial failure of this approach, with a simple and straightforward modification in the matching algorithm, this surface representation works well. Out of the 16 protein-protein complexes we have tried, 15 were successfully docked, including two immunoglobulins. The entire molecular surfaces were considered, with absolutely no additional information regarding the binding sites. The whole process is completely automated, with no manual intervention, either in the input atomic coordinate data, or in the matching. We have been able to reach this level of performance with the hole/knob surface description by using pairs of critical points along with their surface normals in the calculation of the transformation matrix. The success of this approach suggests that future docking methods should use geometric docking as the first screening filter.(ABSTRACT TRUNCATED AT 250 WORDS)

Algorithms↗

PubMed1994

Molecular surface recognition by a computer vision-based technique.

Correct docking of a ligand onto a receptor surface is a complex problem, involving geometry and chemistry. Geometrically acceptable solutions require close contact between corresponding patches of surfaces of the receptor and of the ligand and no overlap between the van der Waals spheres of the remainder of the receptor and ligand atoms. In the quest for favorable chemical interactions, the next step involves minimization of the energy between the docked molecules. This work addresses the geometrical aspect of the problem. It is assumed that we have the atomic coordinates of each of the molecules. In principle, since optimally matching surfaces are sought, the entire conformational space needs to be considered. As the number of atoms residing on molecular surfaces can be several hundred, sampling of all rotations and translations of every patch of a surface of one molecule with respect to the other can reach immense proportions. The problem we are faced with here is reminiscent of object recognition problems in computer vision. Here we borrow and adapt the geometric hashing paradigm developed in computer vision to a central problem in molecular biology. Using an indexing approach based on a transformation invariant representation, the algorithm efficiently scans groups of surface dots (or atoms) and detects optimally matched surfaces. Potential solutions displaying receptor--ligand atomic overlaps are discarded. Our technique has been applied successfully to seven cases involving docking of small molecules, where the structures of the receptor--ligand complexes are available in the crystallographic database and to three cases where the receptors and ligands have been crystallized separately. In two of these three latter tests, the correct transformations have been obtained.

Algorithms↗

PubMed1993

Surface motifs by a computer vision technique: searches, detection, and implications for protein-ligand recognition.

We describe the application of a method geared toward structural and surface comparison of proteins. The method is based on the Geometric Hashing Paradigm adapted from Computer Vision. It allows for comparison of any two sets of 3-D coordinates, such as protein backbones, protein core or protein surface motifs, and small molecules such as drugs. Here we apply our method to 4 types of comparisons between pairs of molecules: (1) comparison of the backbones of two protein domains; (2) search for a predefined 3-D C alpha motif within the full backbone of a domain; and in particular, (3) comparison of the surfaces of two receptor proteins; and (4) comparison of the surface of a receptor to the surface of a ligand. These aspects complement each other and can contribute toward a better understanding of protein structure and biomolecular recognition. Searches for 3-D surface motifs can be carried out on either receptors or on ligands. The latter may result in the detection of pharmacophoric patterns. If the surfaces of the binding sites of either the receptors or of the ligands are relatively similar, surface superpositioning may aid significantly in the docking problem. Currently, only distance invariants are used in the matching, although additional geometric surface invariants are considered. The speed of our Geometric Hashing algorithm is encouraging, with a typical surface comparison taking only seconds or minutes of CPU time on a SUN 4 SPARC workstation. The direct application of this method to the docking problem is also discussed. We demonstrate the success of this method in its application to two members of the globin family and to two dehydrogenases.

Alcohol Dehydrogenase↗

PubMed1991

A model for the adjustment of the mitotic clock by cyclin and MPF levels.

A mathematical model of cell cycle progression is presented, which integrates recent biochemical information on the interaction of the maturation promotion factor (MPF) and cyclin. The model retrieves the dynamics observed in early embryos and explains how multiple cycles of MPF activity can be produced and how the internal clock that determines durations and number of cycles can be adjusted by modulating the rate of change in MPF or cyclin concentrations. Experiments are suggested for verifying the role of MPF activity in determining the length of the somatic cell cycle.

Animals↗