Protein-Ligand Interactions: Energetic Contributions and Shape Complementarity (original) (raw)
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Protein Structures and Complexes: What they Reveal about the Interactions that Stabilize them
Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences, 1993
The rapid increase in the number of high-quality protein structures provides an expanding knowledge resource about interactions involved in stabilizing protein three-dimensional structures and the complexes they form with other molecules. In this paper we first review the results of some recent analyses of protein structure, including restrictions on local conformation, and a study of the geometry of hydrogen bonds. Then we consider how such empirical data can be used as a test bed for energy calculations, by using the observed spatial distributions of side chain/atom interactions to assess three different methods for modelling atomic interactions in proteins. We have also derived a new empirical solvation potential which aims to reproduce the hydrophobic effect. To conclude we address the problem of molecular recognition and consider what we can deduce about the interactions involved in the binding of peptides to proteins.
Shape complementarity at protein-protein interfaces
Biopolymers, 1994
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. 1229-12471. 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 other hand, matchings of fewer critical points require a very time-consuming, full conformational (grid) space search Journal of Computational Chemistry, Vol. 12, pp. 746-7501. 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. As a geometrically based docking methodology predicts correct, along with incorrect, receptorligand bound conformations, all solutions need to undergo energy screening to differentiate between them. 0
Recognition forces in ligand–protein complexes: Blending information from different sources
Biochemical Pharmacology, 2006
b i o c h e m i c a l p h a r m a c o l o g y 7 2 ( 2 0 0 6 ) 1 6 3 3 -1 6 4 5 a r t i c l e i n f o Keywords: Binding Intermolecular forces Hydrophobic effect Solvated systems Crystallography Contacts Abbreviations: a, mean polarizability aq, aqueous state COX-1, cyclooxygenase isoenzyme CSD, Cambridge Structural Database E, internal energy E 0 , electric field F(r), force G, Gibbs free energy g, gas state (or vacuum) H, enthalpy Ĥ , Hamiltonian operator hERG, human ether á go-go related gene MD, molecular dynamics MIF, molecular interaction field r, distance between particles P, pressure PDB, Protein Data Bank p, permanent dipole moment p ind , induced dipole moment q, charge of a particle S, entropy U, potential function V, volume of the system a b s t r a c t A variety of ligands interact with proteins in many biological processes; shape complementarity, electrostatic forces and hydrophobicity are the main factors governing these interactions. Although this is accepted by the scientific community, confusion about the significance of certain terms (e.g. hydrophobicity, salt bridge) and the difficulty of discussing the balance of acting forces rather than their single contributions, are two of the main problems encountered by researchers working in the field. These difficulties are sometimes enhanced by the unskilled use of informatics tools, which give great help in understanding the topic (especially from the visual standpoint), but only if used critically. After explaining some general chemical concepts, the commentary discusses the main forces governing ligand-protein interactions, focusing on those generating confusion among scientists with different backgrounds. Three examples of ligand-protein interactions are then discussed to illustrate the advantages and drawbacks of some in silico tools, highlighting the main interactions responsible for complex formation. The same examples are used to point out the limits in separating forces that are mandatory for occurrence of a given interaction and additional forces. (G. Ermondi). a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b i o c h e m p h a r m 0006-2952/$ -see front matter #
A structural perspective on protein–protein interactions
Current Opinion in Structural Biology, 2004
Structures of macromolecular complexes are necessary for a mechanistic description of biochemical and cellular processes. They can be solved by experimental methods, such as X-ray crystallography, NMR spectroscopy and electron microscopy, as well as by computational protein structure prediction, docking and bioinformatics. Recent advances and applications of these methods emphasize the need for hybrid approaches that combine a variety of data to achieve better efficiency, accuracy, resolution and completeness. Addresses 1 EMBL, : Crystal structure of Thermus aquaticus core RNA polymerase at 3.3 Aresolution. Cell 1999, 98:811-824. 37. Ban N, Nissen P, Hansen J, Moore PB, Steitz TA: The complete atomic structure of the large ribosomal subunit at 2.4 Aresolution. Science 2000, 289:905-920. 38. Carter AP, Clemons WM, Brodersen DE, Morgan-Warren RJ, Wimberly BT, Ramakrishnan V: Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics. Nature 2000, 407:340-348. Structural perspective on protein-protein interactions Russell et al. 319 www.sciencedirect.com Current Opinion in Structural Biology 2004, 14:313-324 104. Gabb HA, Jackson RM, Sternberg MJ: Modelling protein docking using shape complementarity, electrostatics and biochemical information. J Mol Biol 1997, 272:106-120. 105. Moont G, Sternberg MJ: Modeling protein-protein and protein-DNA docking. Edited by Lengauer T. Weinheim: Wiley-VCH; 2001. 106. Jackson RM, Gabb HA, Sternberg MJ: Rapid refinement of protein interfaces incorporating solvation: application to the docking problem. J Mol Biol 1998, 276:265-285. Structural perspective on protein-protein interactions Russell et al. 321 www.sciencedirect.com
Examination of shape complementarity in docking of Unbound proteins
Proteins: Structure, Function, and Genetics, 1999
Here we carry out an examination of shape complementarity as a criterion in proteinprotein docking and binding. Specifically, we examine the quality of shape complementarity as a critical determinant not only in the docking of 26 protein-protein ''bound'' complexed cases, but in particular, of 19 ''unbound'' protein-protein cases, where the structures have been determined separately. In all cases, entire molecular surfaces are utilized in the docking, with no consideration of the location of the active site, or of particular residues/ atoms in either the receptor or the ligand that participate in the binding. To evaluate the goodness of the strictly geometry-based shape complementarity in the docking process as compared to the main favorable and unfavorable energy components, we study systematically a potential correlation between each of these components and the root mean square deviation (RMSD) of the ''unbound'' protein-protein cases. Specifically, we examine the non-polar buried surface area, polar buried surface area, buried surface area relating to groups bearing unsatisfied buried charges, and the number of hydrogen bonds in all docked protein-protein interfaces. For these cases, where the two proteins have been crystallized separately, and where entire molecular surfaces are considered without a predefinition of the binding site, no correlation is observed. None of these parameters appears to consistently improve on shape complementarity in the docking of unbound molecules. These findings argue that simplicity in the docking process, utilizing geometrical shape criteria may capture many of the essential features in protein-protein docking. In particular, they further reinforce the long held notion of the importance of molecular surface shape complementarity in the binding, and hence in docking. This is particularly interesting in light of the fact that the structures of the docked pairs have been determined separately, allowing side chains on the surface of the proteins to move relatively freely.
2015
Understanding the physical and chemical principles governing specificity and promiscuity in protein—protein binding is important both for understanding mechanisms of molecular recognition and for designing novel biomolecular systems. The goal of this project is to identify if the energetic contributions of structural moieties (e.g., side chains and backbones of individual residues) are different between promiscuous and specific protein—protein interactions. To achieve this goal, we are testing multiple hypotheses; for example, we hypothesize that specific proteins, which selectively bind to only one partner, preferentially utilize side chains to mediate binding when compared to promiscuous proteins, which may utilize the structurally consistent backbone moieties more preferentially. Electrostatic contributions of the structural moieties toward binding are quantified using component analysis techniques within a continuum electrostatic framework that takes solvent effects into account...
Journal of Medicinal Chemistry, 2002
The prediction of the binding affinity between a protein and ligands is one of the most challenging issues for computational biochemistry and drug discovery. While the enthalpic contribution to binding is routinely available with molecular mechanics methods, the entropic contribution is more difficult to estimate. We describe and apply a relatively simple and intuitive calculation procedure for estimating the free energy of binding for 53 protein-ligand complexes formed by 17 proteins of known three-dimensional structure and characterized by different active site polarity. HINT, a software model based on experimental LogP o/w values for small organic molecules, was used to evaluate and score all atom-atom hydropathic interactions between the protein and the ligands. These total scores (H TOTAL ), which have been previously shown to correlate with ∆G interaction for protein-protein interactions, correlate with ∆G binding for protein-ligand complexes in the present study with a standard error of (2.6 kcal mol -1 from the equation ∆G binding ) -0.001 95 H TOTAL -5.543. A more sophisticated model, utilizing categorized (by interaction class) HINT scores, produces a superior standard error of (1.8 kcal mol -1 . It is shown that within families of ligands for the same protein binding site, better models can be obtained with standard errors approaching (1.0 kcal mol -1 . Standardized methods for preparing crystallographic models for hydropathic analysis are also described. Particular attention is paid to the relationship between the ionization state of the ligands and the pH conditions under which the binding measurements are made. Sources and potential remedies of experimental and modeling errors affecting prediction of ∆G binding are discussed.
Conformational energy penalties of protein-bound ligands
Journal of computer-aided molecular design, 1998
The conformational energies required for ligands to adopt their bioactive conformations were calculated for 33 ligand-protein complexes including 28 different ligands. In order to monitor the force field dependence of the results, two force fields, MM3* and AMBER*, were employed for the calculations. Conformational analyses were performed in vacuo and in aqueous solution by using the generalized Born/solvent accessible surface (GB/SA) solvation model. The protein-bound conformations were relaxed by using flat-bottomed Cartesian constraints. For about 70% of the ligand-protein complexes studied, the conformational energies of the bioactive conformations were calculated to be < or = 3 kcal/mol. It is demonstrated that the aqueous conformational ensemble for the unbound ligand must be used as a reference state in this type of calculations. The calculations for the ligand-protein complexes with conformational energy penalties of the ligand calculated to be larger than 3 kcal/mol suff...
Hydrogen Bonding and Molecular Surface Shape Complementarity as a Basis for Protein Docking
Journal of Molecular Biology, 1996
A geometric docking algorithm based upon correlation analysis for GBF (Gesellschaft für quantification of geometric complementarity between protein molecular Biotechnologische Forschung) Abt., Molekulare surfaces in close interfacial contact has been developed by a detailed Strukturforschung optimization of the conformational search of the algorithm. In order to reduce the entire conformation space search required by the method a Mascheroder Weg 1, D-38124 physico-chemical pre-filter of conformation space has been developed Braunschweig, Germany based upon the a priori assumption that two or more intermolecular hydrogen bonds are intrinsic to the mechanism of binding within protein complexes. Donor sites are defined spatially and directionally by the positions of explicitly calculated donor hydrogen atoms, and the vector space within a defined range about the donor atom-hydrogen atom bond vector. Acceptor sites are represented spatially and directionally by the van der Waals molecular surface points having normal vectors within a predefined range of vector space about the acceptor atom covalent bond vector(s). Geometric conditions necessary for the simultaneous hydrogen bonding interaction between both sites of functionally congruent hydrogen bonding site pairs, located on the individual proteins, are then tested on the basis of a transformation invariant parameterization of the site pair spatial and directional properties. Sterically acceptable conformations defined by interaction of functionally, spatially, and directionally compatable site pairs are then refined to a maximum contact of complementary contact surfaces using the simplex method for the angular search and correlation techniques for the translational search. The utility of the spatial and directional properties of hydrogen bonding donor and acceptor sites for the identification of candidate docking conformations is demonstrated by the reliable preliminary reduction of conformation space, the improved geometric ranking of the minimum RMS conformations of some complexes and the overall reduction of CPU time obtained.