Geometric Complementarity Research Articles

Carbamate-appended Zn-porphyrin: a neutral receptor for anions

A new neutral anion receptor that contains a unique combination of an immobilized Lewis acidic binding site and carbamate groups enabling additional hydrogen bonds with a coordinated anion guest has been developed. UV–vis titration binding studies revealed the free-base porphyrin 1 and ZnTPP to be poor complexing agents for anions. In contrast, the zinc metalloporphyrin receptor 2 strongly bound anionic guests and selectivity trends turned out to be dependent upon the anion basicity and geometrical complementarity between 2 and the guest.

BiGGER: A new (soft) docking algorithm for predicting protein interactions

A new computationally efficient and automated "soft docking" algorithm is described to assist the prediction of the mode of binding between two proteins, using the three-dimensional structures of the unbound molecules. The method is implemented in a software package called BiGGER (Bimolecular Complex Generation with Global Evaluation and Ranking) and works in two sequential steps: first, the complete 6-dimensional binding spaces of both molecules is systematically searched. A population of candidate protein-protein docked geometries is thus generated and selected on the basis of the geometric complementarity and amino acid pairwise affinities between the two molecular surfaces. Most of the conformational changes observed during protein association are treated in an implicit way and test results are equally satisfactory, regardless of starting from the bound or the unbound forms of known structures of the interacting proteins. In contrast to other methods, the entire molecular surfaces are searched during the simulation, using absolutely no additional information regarding the binding sites. In a second step, an interaction scoring function is used to rank the putative docked structures. The function incorporates interaction terms that are thought to be relevant to the stabilization of protein complexes. These include: geometric complementarity of the surfaces, explicit electrostatic interactions, desolvation energy, and pairwise propensities of the amino acid side chains to contact across the molecular interface. The relative functional contribution of each of these interaction terms to the global scoring function has been empirically adjusted through a neural network optimizer using a learning set of 25 protein-protein complexes of known crystallographic structures. In 22 out of 25 protein-protein complexes tested, near-native docked geometries were found with C(alpha) RMS deviations < or =4.0 A from the experimental structures, of which 14 were found within the 20 top ranking solutions. The program works on widely available personal computers and takes 2 to 8 hours of CPU time to run any of the docking tests herein presented. Finally, the value and limitations of the method for the study of macromolecular interactions, not yet revealed by experimental techniques, are discussed.

Grafting of Protein-Protein Interaction Epitope

Transferring the biological function of one protein to another is a key issue in understanding the structure and function relationship of proteins. We have developed a strategy for grafting protein-protein interaction epitopes. As a first step, residues at the interface of the ligand protein which strongly interact with the receptor protein were identified. Then protein scaffolds were docked onto receptor protein based on geometric complementarity. Only high docking score matches were saved. For each saved match, the scaffold protein was accepted if it had suitable positions for grafting key interaction residues of the ligand protein. These candidate residues were mutated to corresponding residues in the ligand protein at each relevant position and the mutated scaffold protein was co-minimized with receptor protein. Finally, the minimized complexes were evaluated by a scoring function deduced from statistical analysis of rigid binding data sets. As a test case, the binding epitope of barstar, the inhibitor of barnase, was grafted onto smaller proteins. Pheromone Er-1(PDB entry 1erc) has been found to be a good scaffold. The calculated binding free energy for mutated Pheromone Er-1 is equivalent to that of barstar.

Revised Interpretation of Work Potential in Thermophysical Processes

An alternative development is attempted of the concept of exergy or availability by introducing the idea that exergy represents an abstract thermodynamic metric that, essentially, quantie es the distance from the state of equilibrium with respect to a given reference value. Traditional and textbook approaches usually develop exergy asasystem’ spotentialtodoreversiblework.Usually,combiningthebalanceofenergyandentropyequationsmakes it possible to construct a corresponding balance of exergy and to use its dee nition to interpret the resulting terms. In contrast, the essential elements presented deal with the mathematical property of concavity of the entropy as the essence of the second law and how this property translates into a geometric complementarity relation between entropy and exergy. The balance of exergy equation is presented as an expression representing the corresponding convexity of the exergy, again demonstrating a mathematical property intrinsic to the second law. Nomenclature E = total energy density e = total specie c energy g = gravitational acceleration constant H = enthalpy density h = specie c enthalpy I = e ux or current of quantity k = coefe cient of thermal conductivity M = molecular mass m = mass P = thermodynamic pressure = thermal energy transfer rate (heating) R = gas constant S = entropy density s = specie c entropy T = temperature t = time U = internal energy density u = specie c internal energy V = volume = e uid velocity v = specie c volume = mechanical energy transfer rate (working) X = exergy density (also known as availability ) xk = Cartesian coordinates z = elevation level in a gravitational e eld b = thermal expansion coefe cient c = ratio of specie c heats D = total change in quantity d ij = Kronecker delta j = isothermal compressibility k = second coefe cient of viscosity l = e rst coefe cient of viscosity n = generic variable q = mass density s ij = viscous stress tensor u = specie c exergy w = specie c e ow exergy

Heteronuclear NMR and soft docking: an experimental approach for a structural model of the cytochrome c553-ferredoxin complex.

The combination of docking algorithms with NMR data has been developed extensively for the studies of protein-ligand interactions. However, to extend this development for the studies of protein-protein interactions, the intermolecular NOE constraints, which are needed, are more difficult to access. In the present work, we describe a new approach that combines an ab initio docking calculation and the mapping of an interaction site using chemical shift variation analysis. The cytochrome c553-ferredoxin complex is used as a model of numerous electron-transfer complexes. The 15N-labeling of both molecules has been obtained, and the mapping of the interacting site on each partner, respectively, has been done using HSQC experiments. 1H and 15N chemical shift analysis defines the area of both molecules involved in the recognition interface. Models of the complex were generated by an ab initio docking software, the BiGGER program (bimolecular complex generation with global evaluation and ranking). This program generates a population of protein-protein docked geometries ranked by a scoring function, combining relevant stabilization parameters such as geometric complementarity surfaces, electrostatic interactions, desolvation energy, and pairwise affinities of amino acid side chains. We have implemented a new module that includes experimental input (here, NMR mapping of the interacting site) as a filter to select the accurate models. Final structures were energy minimized using the X-PLOR software and then analyzed. The best solution has an interface area (1037.4 A2) falling close to the range of generally observed recognition interfaces, with a distance of 10.0 A between the redox centers.

New molecular catalysts for ATP cleavage. Criteria of size complementarity

The interaction of the cyclophane receptor 2,5,8,11,14,17-hexaaza[18]metacyclophane (L) with the nucleotides ATP, ADP and AMP is described. L yields one of the largest rate enhancements for hydrolytic ATP cleavage observed in macrocyclic polyamines. The process is specific for the formation of ADP and involves a high degree of geometrical complementarity between host and guest species. The analogue compound 24-hydroxy-2,5,8,11,14,17-hexaaza[18]metacyclophane (L11) shows also a high degree of ATP activation. However, in this case deprotonation of the hydroxy group results in almost complete quenching of the ATPase activity above pH 7.0.

Protonated azacryptate hosts for nitrate and perchlorate

Encapsulation of nitrate and perchlorate within two protonated cryptate hosts [H6L1]6+ and [H6L2]6+, as studied by potentiometric and NMR titration methods, showed dominant 1∶1 complexation for both anions. Complexation constants, log K, with [H6L1]6+ and [H6L2]6+ are, generally, high at 3.7 and 3.4 for nitrate, and ≈3.4 and ≈2.5 for perchlorate, respectively. Good geometric complementarity was confirmed in the case of perchlorate and [H6L2]6+ by an X-ray crystallographic structure determination of the inclusive anion cryptate. For nitrate, there is evidence for 1∶2 complexation in the presence of a large excess of anion, relative 1∶1 and 1∶2 complexation constants being in the approximate ratio 103∶1.

Dynamic Combinatorial Chemistry: Substrate H-Bonding Directed Assembly of Receptors Based on Bipyridine-Metal Complexes

The functionalized ligands 1 and 2 bearing hydrogenmoderate selective increase of the fraction of the [(1a)2Cu] or [(1b)2Pd] complex depending on the Janus substrate bonding recognition groups have been synthesized. Their assembly by metal ions such as CuI and PdII having different used. Largest enhancements are observed for those Janus substrates that may be expected to display highest coordination geometries generates different receptor architectures for the binding of suitable substrates. Addition geometrical complementarity with the two complexes. These results represent a process directed by target binding based of the complementary bis(imide) Janus molecules (4–7) to [1a, 2a, CuTf] or to [1b, 2b, Pd(BF4)2] mixtures leads to a on dynamic combinatorial chemistry.

Minor Groove Interactions between Polymerase and DNA: More Essential to Replication than Watson−Crick Hydrogen Bonds?

Minor Groove Interactions between Polymerase and DNA: More Essential to Replication than Watson−Crick Hydrogen Bonds?

Supramolecular Structures – Reason and Imagination

Supramolecular chemistry is the chemistry of the intermolecular bond and is based on the theme of mutual recognition. Such recognition is characterized by chemical and geometrical complementarity between interacting molecules. With the awareness that an organic crystal may be treated as a supermolecule, crystal engineering, the design of crystal structures, may be considered as a supramolecular equivalent of organic synthesis. Crystal engineering has been developed by structural chemists and crystallographers to better understand noncovalent interactions for the design of novel materials and solid-state reactions. The subject consists of two main components, analysis and synthesis, and because of this its resemblance to classical organic chemistry is marked. The concepts and principles of recognition and the nature of the interactions that mediate supramolecular construction in the solid state constitute the analytical component while the synthetic component consists of the strategies employed in the design of solids with particular topological and functional properties. Reason and imagination therefore come into play simultaneously in the quest for new functionalized solids.

Molecular Origins of Osmotic Second Virial Coefficients of Proteins

The thermodynamic properties of protein solutions are determined by the molecular interactions involving both solvent and solute molecules. A quantitative understanding of the relationship would facilitate more systematic procedures for manipulating the properties in a process environment. In this work the molecular basis for the osmotic second virial coefficient, B 22, is studied; osmotic effects are critical in membrane transport, and the value of B 22 has also been shown to correlate with protein crystallization behavior. The calculations here account for steric, electrostatic, and short-range interactions, with the structural and functional anisotropy of the protein molecules explicitly accounted for. The orientational dependence of the protein interactions is seen to have a pronounced effect on the calculations; in particular, the relatively few protein-protein configurations in which the apposing surfaces display geometric complementarity contribute disproportionately strongly to B 22. The importance of electrostatic interactions is also amplified in these high-complementarity configurations. The significance of molecular recognition in determining B 22 can explain the correlation with crystallization behavior, and it suggests that alteration of local molecular geometry can help in manipulating protein solution behavior. The results also have implications for the role of protein interactions in biological self-organization.

An infeasible-interior-point predictor-corrector algorithm for theP *-geometric LCP

AP *-geometric linear complementarity problem (P *GP) as a generalization of the monotone geometric linear complementarity problem is introduced. In particular, it contains the monotone standard linear complementarity problem and the horizontal linear complementarity problem. Linear and quadratic programming problems can be expressed in a “natural” way (i.e., without any change of variables) asP *GP. It is shown that the algorithm of Mizunoet al. [6] can be extended to solve theP *GP. The extended algorithm is globally convergent and its computational complexity depends on the quality of the starting points. The algorithm is quadratically convergent for problems having a strictly complementary solution.

Escher: A new docking procedure applied to the reconstruction of protein tertiary structure

Evaluation of Surface Complementarity, Hydrogen bonding, and Electrostatic interaction in molecular Recognition (ESCHER) is a new docking procedure consisting of three modules that work in series. The first module evaluates the geometric complementarity and produces a set of rough solutions for the docking problem. The second module identifies molecular collisions within those solutions, and the third evaluates their electrostatic complementarity. We describe the algorithm and its application to the docking of cocrystallized protein domains and unbound components of protein-protein complexes. Furthermore, ESCHER has been applied to the reassociation of secondary and supersecondary structure elements. The possibility of applying a docking method to the problem of protein structure prediction is discussed. Proteins 28:556–567, 1997. © 1997 Wiley-Liss, Inc.

Polypeptide Interactions at Ice and Biomineral Interfaces Are Defined by Secondary Structure-Dependent Chain Orientations

The stereospecific interaction of polypeptides with biominerals and ice represents a unique phenomenon in nature. Here, using the theoretical geometric lattice matching algorithm, CHASM (abbreviation for chain alignment on the surface of materials), we explore the geometric complementarity of specific Cα polypeptide secondary structures (α-helix, β-sheet, γ-turn) with the [001] planes of the biominerals, aragonite and calcite, and the [001], [100], and [201] faces of hexagonal ice. We find that certain secondary structure−surface pairings exhibit a defined set of orientational minima that agree closely with published results. Moreover, no two secondary structures feature the exact same set of global and local orientational minima for a given surface. This suggests that the molecular complementarity of each secondary structure with a given surface is highly specific and cannot be mimicked by another secondary structure. These results suggest that the site and orientation of polypeptide adsorption onto biominerals or ice may be influenced by secondary structure type.

Escher: A new docking procedure applied to the reconstruction of protein tertiary structure

Evaluation of Surface Complementarity, Hydrogen bonding, and Electrostatic interaction in molecular Recognition (ESCHER) is a new docking procedure consisting of three modules that work in series. The first module evaluates the geometric complementarity and produces a set of rough solutions for the docking problem. The second module identifies molecular collisions within those solutions, and the third evaluates their electrostatic complementarity. We describe the algorithm and its application to the docking of cocrystallized protein domains and unbound components of protein-protein complexes. Furthermore, ESCHER has been applied to the reassociation of secondary and supersecondary structure elements. The possibility of applying a docking method to the problem of protein structure prediction is discussed.

Electrostatic complementarity at protein/protein interfaces

Calculation of the electrostatic potential of protein-protein complexes has led to the general assertion that protein-protein interfaces display “charge complementarity” and “electrostatic complementarity”. In this study, quantitative measures for these two terms are developed and used to investigate protein-protein interfaces in a rigorous manner. Charge complementarity (CC) was defined using the correlation of charges on nearest neighbour atoms at the interface. All 12 protein-protein interfaces studied had insignificantly small CC values. Therefore, the term charge complementarity is not appropriate for the description of protein-protein interfaces when used in the sense measured by CC. Electrostatic complementarity (EC) was defined using the correlation of surface electrostatic potential at protein-protein interfaces. All twelve protein-protein interfaces studied had significant EC values, and thus the assertion that protein-protein association involves surfaces with complementary electrostatic potential was substantially confirmed. The term electrostatic complementarity can therefore be used to describe protein-protein interfaces when used in the sense measured by EC. Taken together, the results for CC and EC demonstrate the relevance of the long-range effects of charges, as described by the electrostatic potential at the binding interface. The EC value did not partition the complexes by type such as antigen-antibody and proteinase-inhibitor, as measures of the geometrical complementarity at protein-protein interfaces have done. The EC value was also not directly related to the number of salt bridges in the interface, and neutralisation of these salt bridges showed that other charges also contributed significantly to electrostatic complementarity and electrostatic interactions between the proteins. Electrostatic complementarity as defined by EC was extended to investigate the electrostatic similarity at the surface of influenza virus neuraminidase where the epitopes of two monoclonal antibodies, NC10 and NC41, overlap. Although NC10 and NC41 both have quite high values of EC for their interaction with neuraminidase, the similarity in electrostatic potential generated by the two on the overlapping region of the epitopes is insignificant. Thus, it is possible for two antibodies to recognise the electrostatic surface of a protein in dissimilar ways.

De novo design of native proteins: characterization of proteins intended to fold into antiparallel, rop-like, four-helix bundles.

The de novo design and characterization of a series of 51-residue helix-turn-helix peptides intended to dimerize into antiparallel four-stranded coiled coils is described. The sequence is based on a coiled coil heptad repeat Ncap-(Aa Zb Zc Ld Ze Zf Zg)3-turn- (Xa Zb Zc Ld Ze Zf Zg)3-Ccap-CONH2, where X is either Val or Ala. The overall topology was intended to be similar to that found in the Escherichia coli protein ROP. The design strategy included consideration of geometric complementarity of the packing of side chains within the hydrophobic core as well as the use of specific interfacial interactions, both of which were intended to favor the desired ROP-like topology. Additionally, the sequence was designed to destabilize potential alternative structures that might compete with the desired topology. The peptides (RLP-1, RLP-2, and RLP-3) assemble into stable alpha-helical dimers and exhibit the hallmarks of a native protein as judged by its spectroscopic properties, and the lack of binding to hydrophobic dyes. Also, the enthalpy and heat capacity changes upon denaturation were determined by measuring the temperature dependence of the CD spectra and confirmed by differential scanning calorimetry (DSC). The values determined by the two methods are in excellent agreement and are in the range of those of naturally occurring proteins of this size. These results suggest that it is now possible to design native-like helical proteins that should serve as templates for the further design of functional proteins.

Hydrogen Bonding and Molecular Surface Shape Complementarity as a Basis for Protein Docking

A geometric docking algorithm based upon correlation analysis for quantification of geometric complementarity between protein molecular surfaces in close interfacial contact has been developed by a detailed optimization of the conformational search of the algorithm. In order to reduce the entire conformation space search required by the method a physico-chemical pre-filter of conformation space has been developed based upon the a prioriassumption 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.

Catalysis in Drug Design and Medicinal Chemistry

The pathophysiology observed in an array of human diseases is the result primarily of the aberrant activity of one or more enzymes. Thus, understanding the biochemical basis underlying a disease invariably paves the way toward the development of therapeutic agents capable of arresting or modulating the deleterious activity of a target enzyme. It also places the design of these agents on a sound biochemical footing. Rational drug design is a complex task involving the application of the fundamental principles of mechanistic enzymology and physical organic chemistry in the development of therapeutic agents. An integral part of this process is the use of a range of powerful tools, including x-ray crystallography, computational chemistry and computer graphics and modeling, structureactivity relationship studies, molecular biology, nuclear magnetic resonance spectroscopy, etc. (Bugg, Carson, and Montgomery, 1993). Therapeutic agents that exert their action by blocking the action of an enzyme, may consist of a single recognition component, as in competitive inhibitors, or a recognition component tethered to a reactive center (Weinbaum and Groutas, 1991). Frequently, the recognition component is a small peptide chain the selection of which is based on the known substrate specificity of the target enzyme. The reactive center may embody latent reactivity, as is the situation with mechanism-based inhibitors (Abell, 1992). Geometric and charge complementarity are two salient features common to both substrates and inhibitors. Some examples illustrating these principles are given here.

Structural basis for multiple ligand specificity of the periplasmic lysine-, arginine-, ornithine-binding protein

The substrate-binding site of a protein with multiple specificity should satisfy geometric and energetic complementarity for several different substrates. The structural basis of the multiple ligand specificity of the periplasmic lysine-, arginine-, ornithine-binding protein (LAO) was investigated by determining and analyzing the structures of the protein unliganded and liganded with each of the three high-affinity ligands (L-lysine, L-arginine, and L-ornithine) and with one low-affinity ligand (L-histidine). The geometric complementarity is achieved primarily by virtue of the large size of the ligand-binding site which can accommodate the maximum common volume of the four ligands plus three water molecules. The optimization of energetic complementarity is achieved by the relocation of protein-bound water molecules and by the movement of the Asp-11 side chain. The structure of the LAO-histidine complex indicates that the 30-fold reduced affinity of the protein for histidine is primarily due to unavailability of one ionic interaction of the histidine side chain with the protein which is present in the other three complexes.