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PubMed2002

Exploration of molecular interactions in cholesterol superlattices: effect of multibody interactions.

Experimental evidences have indicated that cholesterol may adapt highly regular lateral distributions (i.e., superlattices) in a phospholipid bilayer. We investigated the formations of superlattices at cholesterol mole fraction of 0.154, 0.25, 0.40, and 0.5 using Monte Carlo simulation. We found that in general, conventional pairwise-additive interactions cannot produce superlattices. Instead, a multibody (nonpairwise) interaction is required. Cholesterol superlattice formation reveals that although the overall interaction between cholesterol and phospholipids is favorable, it contains two large opposing components: an interaction favoring cholesterol-phospholipid mixing and an unfavorable acyl chain multibody interaction that increases nonlinearly with the number of cholesterol contacts. The magnitudes of interactions are in the order of kT. The physical origins of these interactions can be explained by our umbrella model. They most likely come from the requirement for polar phospholipid headgroups to cover the nonpolar cholesterol to avoid the exposure of cholesterol to water and from the sharp decreasing of acyl chain conformation entropy due to cholesterol contact. This study together with our previous work demonstrate that the driving force of cholesterol-phospholipid mixing is a hydrophobic interaction, and multibody interactions dominate others over a wide range of cholesterol concentration.

Biophysical Phenomena↗

PubMed1999

Thermodynamics of interactions between amino acid side chains: experimental differentiation of aromatic-aromatic, aromatic-aliphatic, and aliphatic-aliphatic side-chain interactions in water.

A stationary phase for high-pressure liquid chromatography has been prepared by derivatizing microparticulate silica gel with functionality mimicking the side chain of isoleucine. The chromatographic retentions of a series of hydrophobic and amphiphilic amino acid analytes on this stationary phase (Ile MSP) using an aqueous mobile phase were measured as a function of temperature from 273 K to 323 K. Observed temperature dependencies are consistent with a constant change in heat capacity, DeltaC degrees P, upon binding of the analyte to the stationary phase. The curvatures of plots of retention data versus temperature (related to the magnitude of DeltaC degrees P) are distinctly different for retention of aromatic and aliphatic analytes, with retention of aliphatic analytes Val, Ile, and Leu exhibiting the characteristic signature of the hydrophobic effect, i.e., a large negative DeltaC degrees P upon desolvation from water and a maximum of retention around room temperature. Retention of aromatic analytes (Trp, Phe, and Tyr) involves smaller heat capacity changes and pronounced negative enthalpies of interaction with the stationary phase. Estimates of DeltaC degrees P for the interactions of analyte side chains with the Ile side chain were obtained by fitting the temperature dependence of retention to an expression derived from thermodynamic considerations and chromatographic theory. Similar estimates were made for interactions with the Phe side chain, using previously published data for a phenylalanine mimic stationary phase (Phe MSP) (. Protein Sci. 1:786-795). As with the Ile MSP, the retentions of aliphatic analytes show temperature dependencies markedly different from those of aromatic analytes. Data from both phases indicate that a realistic differentiation can be made between the interactions of various types of amino acid side chains tested (i.e., aliphatic/aliphatic, aliphatic/aromatic, and aromatic/aromatic) by comparison of the corresponding thermodynamic functions for pairwise interactions. The retention of leucine on the Phe MSP and that of phenylalanine on the Ile MSP showed similar DeltaC degrees P values, suggesting that the aromatic-aliphatic interaction is reasonably independent of the residue attached to the stationary phase. This result is consistent with a one-to-one interaction and suggests a simple way to estimate the column-dependent phase factor, making it possible to compare entropies and free energies of interaction obtained using different MSPs. The possibilities for using MSP-derived interaction potentials in folding simulations are discussed.

Amino Acids↗

PubMed2003

Homotypic interactions of the infectious bursal disease virus proteins VP3, pVP2, VP4, and VP5: mapping of the interacting domains.

Infectious bursal disease virus (IBDV), a nonenveloped double-stranded RNA virus of chicken, encodes five proteins. Of these, the RNA-dependent RNA polymerase (VP1) is specified by the smaller genome segment, while the large segment directs synthesis of a nonstructural protein (VP5) and a structural protein precursor from which the capsid proteins pVP2 and VP3 as well as the viral protease VP4 are derived. Using the recently redefined processing sites of the precursor, we have reevaluated the homotypic interactions of the viral proteins using the yeast two-hybrid system. Except for VP1, which interacted weakly, all proteins appeared to self-associate strongly. Using a deletion mutagenesis approach, we subsequently mapped the interacting domains in these polypeptides, where possible confirming the observations made in the two-hybrid system by performing coimmunoprecipitation analyses of tagged protein constructs coexpressed in avian culture cells. The results revealed that pVP2 possesses multiple interaction domains, consistent with available structural information about this external capsid protein. VP3-VP3 interactions were mapped to the amino-terminal part of the polypeptide. Interestingly, this domain is distinct from two other interaction domains occurring in this internal capsid protein: while binding to VP1 has been mapped to the carboxy-terminal end of the protein, interaction with the genomic dsRNA segments has been suggested to occur just upstream thereof. No interaction sites could be assigned to the VP4 protein; any deletion applied abolished its self-association. Finally, one interaction domain was detected in the central, most hydrophobic region of VP5, supporting the idea that this virulence determinant may function as a membrane pore-forming protein in infected cells.

Animals↗

PubMed2006

A system for quantifying dynamic protein interactions defines a role for Herceptin in modulating ErbB2 interactions.

The orphan receptor tyrosine kinase ErbB2 is activated by each of the EGFR family members upon ligand binding. However, difficulties monitoring the dynamic interactions of the membrane receptors have hindered the elucidation of the mechanism of ErbB2 activation. We have engineered a system to monitor protein-protein interactions in intact mammalian cells such that different sets of protein interactions can be quantitatively compared. Application of this system to the interactions of the EGFR family showed that ErbB2 interacts stably with the EGFR and ErbB3, but fails to spontaneously homooligomerize. The widely used anti-cancer antibody Herceptin was found to effectively inhibit the interaction of the EGFR and ErbB2 but not to interfere with the interaction of ErbB2-ErbB3. Treatment of cells expressing EGFR and ErbB2 with Herceptin results in increased EGFR homooligomerization in the presence of EGF and a subsequent rapid internalization and down-regulation of the EGFR. In summary, the protein interaction system described here enabled the characterization of ErbB2 interactions within the biological context of the plasma membrane and provides insight into the mechanism of Herceptin action on cells overexpressing ErbB2.

Antibodies, Monoclonal↗

PubMed2000

AvrPto-dependent Pto-interacting proteins and AvrPto-interacting proteins in tomato.

The plant-intracellular interaction of the avirulence protein AvrPto of Pseudomonas syringae pathovar tomato, the agent of bacterial speck disease, and the corresponding tomato resistance protein Pto triggers responses leading to disease resistance. Pto, a serine/threonine protein kinase, also interacts with a putative downstream kinase, Pto-interactor 1, as well as with members of a family of transcription factors Pto-interactors 4, 5, and 6. These proteins are likely involved, respectively, in a phosphorylation cascade resulting in hypersensitive cell death, and in defense gene activation. The mechanism by which the interaction of AvrPto and Pto initiates defense response signaling is not known. To pursue the hypothesis that tertiary interactions are involved, we modified the yeast two-hybrid protein interaction trap and conducted a search for tomato proteins that interact with Pto only in the presence of AvrPto. Five classes of AvrPto-dependent Pto interactors were isolated, and their interaction specificity confirmed. Also, to shed light on a recently demonstrated virulence activity of AvrPto, we conducted a standard two-hybrid screen for tomato proteins in addition to Pto that interact with AvrPto: i.e., potential virulence targets or modifiers of AvrPto. By constructing an N-terminal rather than a C-terminal fusion of AvrPto to the LexA DNA binding domain, we were able to overcome autoactivation by AvrPto and identify four classes of specific AvrPto-interacting proteins.

Amino Acid Sequence↗

PubMed2004

Hox transcription factor ultrabithorax Ib physically and genetically interacts with disconnected interacting protein 1, a double-stranded RNA-binding protein.

The Hox protein family consists of homeodomain-containing transcription factors that are primary determinants of cell fate during animal development. Specific Hox function appears to rely on protein-protein interactions; however, the partners involved in these interactions and their function are largely unknown. Disconnected Interacting Protein 1 (DIP1) was isolated in a yeast two-hybrid screen of a 0-12-h Drosophila embryo library designed to identify proteins that interact with Ultrabithorax (Ubx), a Drosophila Hox protein. The Ubx.DIP1 physical interaction was confirmed using phage display, immunoprecipitation, pull-down assays, and gel retardation analysis. Ectopic expression of DIP1 in wing and haltere imaginal discs malforms the adult structures and enhances a decreased Ubx expression phenotype, establishing a genetic interaction. Ubx can generate a ternary complex by simultaneously binding its target DNA and DIP1. A large region of Ubx, including the repression domain, is required for interaction with DIP1. These more variable sequences may be key to the differential Hox function observed in vivo. The Ubx.DIP1 interaction prevents transcriptional activation by Ubx in a modified yeast one-hybrid assay, suggesting that DIP1 may modulate transcriptional regulation by Ubx. The DIP1 sequence contains two dsRNA-binding domains, and DIP1 binds double-stranded RNA with a 1000-fold higher affinity than either single-stranded RNA or double-stranded DNA. The strong interaction of Ubx with an RNA-binding protein suggests a wider range of proteins may influence Ubx function than previously appreciated.

Animals↗

PubMed2005

Distributional interaction: Interpretational problems when using incidence odds ratios to assess interaction.

It is well known that the incidence odds ratio approximates the risk ratio when the disease of interest is rare, but increasingly overestimates the risk ratio as the disease becomes more common. However when assessing interaction, incidence odds ratios may not approximate risk ratios even when the disease is rare. We use the term "distributional interaction" to refer to interaction that appears when using incidence odds ratios that does not appear, or appears to a lesser degree, when using risk ratios. The interpretational problems that arise from this discrepancy can have important implications in epidemiologic research. Therefore, quantification of the relationship between the interaction odds ratio and the interaction risk ratio is warranted. In this paper, we provide a formula to quantify the differences between incidence odds ratios and risk ratios when they are used to estimate effect modification on a multiplicative scale. Using this formula, we examine the conditions under which these two estimates diverge. Furthermore, we expand this discussion to the implications of using incidence odds ratios to assess effect modification on an additive scale. Finally, we illustrate how distributional interaction arises and the problems that it causes using an example from the literature. Whenever the risk of the outcome variable is non-negligible, distributional interaction is possible. This is true even when the disease is rare (e.g., disease risk is less than 5%). Therefore, when assessing interaction on either an additive or multiplicative scale, caution should be taken in interpreting interaction estimates based on incidence odds ratios.

Journal Article↗

PubMed2002

Enhancement of VDR-mediated transcription by phosphorylation: correlation with increased interaction between the VDR and DRIP205, a subunit of the VDR-interacting protein coactivator complex.

When UMR-106 osteoblastic cells, LLCPK1 kidney cells, and VDR transfected COS-7 cells were transfected with the rat 24-hydroxylase [24(OH)ase] promoter (-1,367/+74) or the mouse osteopontin (OPN) promoter (-777/+79), we found that the response to 1,25dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] could be significantly enhanced 2- to 5-fold by the protein phosphatase inhibitor, okadaic acid (OA). Enhancement of 1,25-(OH)(2)D(3)-induced transcription by OA was also observed using a synthetic reporter gene containing either the proximal 24(OH)ase vitamin D response element (VDRE) or the OPN VDRE, suggesting that the VDRE is sufficient to mediate this effect. OA also enhanced the 1,25-(OH)(2)D(3)-induced levels of 24(OH)ase and OPN mRNA in UMR osteoblastic cells. The effect of OA was not due to an up-regulation of VDR or to an increase in VDR-RXR interaction with the VDRE. To determine whether phosphorylation regulates VDR-mediated transcription by modulating interactions with protein partners, we examined the effect of phosphorylation on the protein-protein interaction between VDR and DRIP205, a subunit of the vitamin D receptor-interacting protein (DRIP) coactivator complex, using glutathione-S-transferase pull-down assays. Similar to the functional studies, OA treatment was consistently found to enhance the interaction of VDR with DRIP205 3- to 4-fold above the interaction observed in the presence of 1,25-(OH)(2)D(3) alone. In addition, studies were done with the activation function-2 defective VDR mutant, L417S, which is unable to stimulate transcription in response to 1,25-(OH)(2)D(3) or to interact with DRIP205. However, in the presence of OA, the mutant VDR was able to activate 24(OH)ase and OPN transcription and to recruit DRIP205, suggesting that OA treatment may result in a conformational change in the activation function-2 defective mutant that creates an active interaction surface with DRIP205. Taken together, these findings suggest that increased interaction between VDR and coactivators such as DRIP205 may be a major mechanism that couples extracellular signals to vitamin D action.

Animals↗

PubMed2006

Development and use of behavior and social interaction software installed on Palm handheld for observation of a child's social interactions with the environment.

In settings in developing countries, children often socialize with multiple socializing agents (peers, siblings, neighbors) apart from their parents, and thus, a measurement of a child's social interactions should be expanded beyond parental interactions. Since the environment plays a role in shaping a child's development, the measurement of child-socializing agents' interactions is important. We developed and used a computerized observational software Behavior and Social Interaction Software (BASIS) with a preloaded coding scheme installed on a handheld Palm device to record complex observations of interactions between children and socializing agents. Using BASIS, social interaction assessments were conducted on 573 preschool children for 1 h in their natural settings. Multiple screens with a set of choices in each screen were designed that included the child's location, broad activity, state, and interactions with child-socializing agents. Data were downloaded onto a computer and systematically analyzed. BASIS, installed on Palm OS (M-125), enabled the recording of the complex interactions of child-socializing agents that could not be recorded with manual forms. Thus, this tool provides an innovative and relatively accurate method for the systematic recording of social interactions in an unrestricted environment.

Activities of Daily Living↗

PubMed1984

T cell-accessory cell interactions that initiate allospecific cytotoxic T lymphocyte responses: existence of both Ia-restricted and Ia-unrestricted cellular interaction pathways.

The specificity of the T-accessory cell interactions that initiate primary allospecific cytotoxic T lymphocyte (CTL) responses were found to be surprisingly diverse and of three distinct major histocompatibility complex (MHC) specificities, involving responder T cell recognition of: a) self-Ia accessory cell determinants, b) allo-Ia accessory cell determinants, or c) allo-K/D accessory cell determinants. Any one of these T-accessory cell interactions was sufficient to initiate allospecific CTL responses. It was observed that when accessory cells did not express foreign class I MHC determinants, primary allospecific CTL responses were invariably initiated by Ia-restricted T-accessory cell interactions. In contrast, it was observed that when accessory cells did express foreign class I MHC determinants, primary allospecific CTL responses could be initiated by Ia-independent T-accessory cell interactions that were specific for allogeneic, but not self, K/D determinants and that did not involve recognition of polymorphic Ia determinants. The MHC specificities of the T-accessory cell interactions that initiate primary allospecific and primary trinitrophenyl (TNP)-self CTL responses were also compared. It was observed that primary allospecific and primary TNP-self CTL responses could be initiated by self-Ia-restricted T-accessory cell interactions, and that in both responses the Ia determinants that the responding T cells recognized as self-specificities on the accessory cell surface were those that their precursors had encountered on radiation-resistant thymic elements in their differentiation environment. In contrast to the initiation of primary TNP-self CTL responses that required the activation by accessory cells of Ia-restricted T helper (TH) cells, allospecific CTL responses could also be initiated by class I-restricted T cells specific for accessory cell K/D determinants. Interestingly, such class I-restricted T cells present in primary responder cell populations were triggered only by recognition of allogeneic, but not self, K/D accessory cell determinants, even when the accessory cells were modified with TNP. Thus, the present study demonstrates that primary allospecific CTL responses, but not TNP-self CTL responses, are initiated by Ia-restricted or Ia-independent cellular interaction pathways. These results raise the possibility that unprimed class I-restricted TH cells that mediate the Ia-independent cellular interaction pathway may predominantly express an allospecific, but not a self + X-specific, receptor repertoire. Possible mechanisms by which these distinct T-accessory cell interactions initiate primary allospecific CTL responses are discuss

Animals↗

PubMed1982

Family free-play interaction: the role of the patient in the family interaction.

We have discussed the salient features of the family interaction in the free-play situation: the high rate of interaction with the child and general predominance of parental initiations in the parent-child interaction, the high correlation among all dyads on warmth. This led to the selection of three variables for study: rate of patient-child interaction, proportion of parental initiations to the child, and family warmth. There are major age changes: rate and proportion both decline with age. The patient's rate of interaction with the child and his proportion of interaction is lower than the spouse's rate. This holds for the 4- and 10-year-olds separately. We have tried to account for its reversal in the 7-year-old sample. Nonpsychotic patients have a higher rate of interaction, higher proportion of interactions, and higher family warmth than psychotics. Affectivity shows no relationship to these variables. Patients with a low global assessment score have lower rates, lower proportion, and less warmth than patients with a higher score. Patients who have been recently hospitalized have a lower rate of interactions with their sons than those who have been hospitalized longer.

Affect↗

PubMed2005

Identification of VCP/p97, carboxyl terminus of Hsp70-interacting protein (CHIP), and amphiphysin II interaction partners using membrane-based human proteome arrays.

Proteins mediate their biological function through interactions with other proteins. Therefore, the systematic identification and characterization of protein-protein interactions have become a powerful proteomic strategy to understand protein function and comprehensive cellular regulatory networks. For the screening of valosin-containing protein, carboxyl terminus of Hsp70-interacting protein (CHIP), and amphiphysin II interaction partners, we utilized a membrane-based array technology that allows the identification of human protein-protein interactions with crude bacterial cell extracts. Many novel interaction pairs such as valosin-containing protein/autocrine motility factor receptor, CHIP/caytaxin, or amphiphysin II/DLP4 were identified and subsequently confirmed by pull-down, two-hybrid and co-immunoprecipitation experiments. In addition, assays were performed to validate the interactions functionally. CHIP e.g. was found to efficiently polyubiquitinate caytaxin in vitro, suggesting that it might influence caytaxin degradation in vivo. Using peptide arrays, we also identified the binding motifs in the proteins DLP4, XRCC4, and fructose-1,6-bisphosphatase, which are crucial for the association with the Src homology 3 domain of amphiphysin II. Together these studies indicate that our human proteome array technology permits the identification of protein-protein interactions that are functionally involved in neurodegenerative disease processes, the degradation of protein substrates, and the transport of membrane vesicles.

Adenosine Triphosphatases↗

PubMed2003

Organization and functions of interacting domains for signaling by protein-protein interactions.

Information transfer from activated heterotrimeric guanine nucleotide-binding proteins (G proteins) to downstream effectors occurs through noncovalent protein-protein interactions. Such interactions involve multiple regions of contact between the G protein and the effector. Some of these regions mediate information transfer, as defined by their ability to change the activity of their downstream binding partners, whereas other interactions appear to contribute solely to binding affinity. Such modular configurations occur in functionally diverse proteins such as myosin and a regulator of the double-stranded DNA stimulated protein kinase (PKR) called PACT. In most cases, it appears that both charge complementarity and the architecture of the interacting surfaces provide the appropriate balance between specificity of interactions and their reversibility. Information transfer regions appear to display conformational flexibility in interactions. Such flexible interactions may be essential for the local conformational changes necessary to induce change in activity by an induced fit-type mechanism. Thus, a general mechanism for information transfer by protein-protein interactions could use specific regions that induce conformation changes in the downstream partner. Other binding regions may be arranged within the protein to impart specificity of recognition and thereby maintain overall contact between the partners during the conformational dynamics that occur in the signal-transfer process.

Models, Structural↗

PubMed1990

Drug interactions involving immunologic agents. Part II. Immunodiagnostic and other immunologic drug interactions.

This two-part review addresses pharmacists' need for information about immunologic drug interactions. Reports of interactions involving vaccines, immune globulins, and immunodiagnostic reagents are widely dispersed and, therefore, difficult to access. In the conclusion of this two-part article, immunodiagnostic drug interactions as well as interactions involving interferons and other biologic-response modifiers are discussed, as are epinephrine interactions that affect treatment of immunologic-induced anaphylaxis. Host factors of groups and individuals relating to the clinical significance of proposed interactions are covered, such as those involving influenza vaccine with theophylline, warfarin, or phenytoin, and other combinations. Vigilance by all pharmacists is needed to detect previously unreported immunologic drug interactions and further assess known interactions.

Drug Interactions↗

PubMed2005

Inferring protein domain interactions from databases of interacting proteins.

We describe domain pair exclusion analysis (DPEA), a method for inferring domain interactions from databases of interacting proteins. DPEA features a log odds score, Eij, reflecting confidence that domains i and j interact. We analyzed 177,233 potential domain interactions underlying 26,032 protein interactions. In total, 3,005 high-confidence domain interactions were inferred, and were evaluated using known domain interactions in the Protein Data Bank. DPEA may prove useful in guiding experiment-based discovery of previously unrecognized domain interactions.

Animals↗

PubMedDate not supplied

Identification of serious drug-drug interactions: results of the partnership to prevent drug-drug interactions.

OBJECTIVE: To develop a list of clinically important drug-drug interactions (DDIs) likely to be encountered in community and ambulatory pharmacy settings and detected by a computerized pharmacy system. DESIGN: Cross-sectional, one-time evaluation. SETTING: United States in fall 2001. PARTICIPANTS: An expert panel comprising two physicians, two clinical pharmacists, and an expert on DDIs. INTERVENTIONS: Systematic review of drug interaction compendia and published literature, ratings (on a 1 to 10 scale) of various clinical aspects of DDIs (e.g., clinical importance, quality and quantity of evidence, causal relationship, risk of morbidity and mortality), and a modified Delphi consensus-building process. MAIN OUTCOME MEASURE: Panelists' opinions about clinical importance of DDIs. RESULTS: The expert panel considered 56 DDIs. Of these, 28 had a mean clinical importance score of 8.0 or more. The ratings for clinical importance ranged from 3.2 to 9.6, with a mean +/- SD of 7.5 +/- 1.5 across the combinations examined. The mean score for the quality of literature suggesting the interaction exists ranged from 1.0 to 9.6, with a mean +/- SD of 5.8 +/- 2.5. In terms of substantiation of the interactions evaluated, the mean +/- SD rating was 6.3 +/- 2.2, with a range from 1.4 to 9.2. Through the modified Delphi process, the panel determined that 25 interactions were clinically important. CONCLUSION: Using an expert panel and a standard evaluation tool, 25 clinically important drug interactions that are likely to occur in the community and ambulatory pharmacy settings were identified. Pharmacists should take steps to prevent patients from receiving these interacting medications, and computer software vendors should focus interaction alerts on these and similarly important DDIs.

Community Pharmacy Services↗

PubMed2001

Effects of the incorporation of CHAPS into SDS micelles on neuropeptide-micelle binding: separation of the role of electrostatic interactions from hydrophobic interactions.

It is well known that neuropeptides interact with lipid vesicles in a manner similar to biological membranes, with electrostatic interactions between the two providing a mechanism for concentrating the peptide at the vesicle's surface, followed by hydrophobic interactions between the peptide and the core of the vesicle that induce and stabilize secondary structure motifs. In an effort to understand these interactions to a greater extent, our group has developed a series of anionic micelles (SDS) containing various concentrations of the bile salt CHAPS, which is used as a model for cholesterol. The incorporation of CHAPS into the hydrophobic core of these micelles should alter the degree to which the neuropeptide can insert itself, affecting structure. These interactions were investigated using two-dimensional NMR, pulse-field gradient (PFG) NMR, and molecular modeling experiments. The results of this study clearly indicate that electrostatic and hydrophobic interactions between the micelle and neuropeptide are completely independent of one another. Increasing the concentration of CHAPS to 15 mM in the micelles blocks the insertion of the hydrophobic side chains of the neuropeptide into the hydrophobic core of the micelles. The electrostatic interactions as determined by diffusion measurements are not affected by the presence of increasing CHAPS concentration. Our observations are consistent with the predictions of Seelig (A. Seelig and J. Seelig, "Interaction of Drugs and Peptides with the Lipid Membrane," in Structure and Function of 7TM Receptors, T. W. Schwartz, S. A. Hjorth, and T. S. Kastrup, Eds., Munksgaard: Location, 1996).

Cholic Acids↗

PubMed2001

SuperStar: comparison of CSD and PDB-based interaction fields as a basis for the prediction of protein-ligand interactions.

SuperStar is an empirical method for identifying interaction sites in proteins, based entirely on the experimental information about non-bonded interactions, present in the IsoStar database. The interaction information in IsoStar is contained in scatterplots, which show the distribution of a chosen probe around structure fragments. SuperStar breaks a template molecule (e.g. a protein binding site) into structural fragments which correspond to those in the scatterplots. The scatterplots are then superimposed on the corresponding parts of the template and converted into a composite propensity map. The original version of SuperStar was based entirely on scatterplots from the CSD. Here, scatterplots based on protein-ligand interactions are implemented in SuperStar, and validated on a test set of 122 X-ray structures of protein-ligand complexes. In this validation, propensity maps are compared with the experimentally observed positions of ligand atoms of comparable types. Although non-bonded interaction geometries in small molecule structures are similar to those found in protein-ligand complexes, their relative frequencies of occurrence are different. Polar interactions are more common in the first class of structures, while interactions between hydrophobic groups are more common in protein crystals. In general, PDB and CSD-based SuperStar maps appear equally successful in the prediction of protein-ligand interactions. PDB-based maps are more suitable to identify hydrophobic pockets, and inherently take into account the experimental uncertainties of protein atomic positions. If the protonation state of a histidine, aspartate or glutamate protein side-chain is known, specific CSD-based maps for that protonation state are preferred over PDB-based maps which represent an ensemble of protonation states.

Databases, Factual↗