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PubMed2001

Monomer-dimer reaction model with asymmetric adsorption of monomer and dimer on the catalyst surface.

The irreversible kinetics of the Ziff-Gulari-Barshad model in the presence of inhomogeneity on a catalyst surface is investigated by means of Monte Carlo simulation. We assume that only part of catalyst surface sites are active for surface catalytic reaction and randomly distributed on the catalyst surface. The adsorption of a O2 molecule is permitted if one site of a nearest-neighbor vacant pair is active. CO can adsorb on all vacant sites, but the adsorption probability is p(p<1) if the site is not active. In our modified model, the O-passivated phase disappears and the continuous phase transition between the O passivated and the reactive state is eliminated. We also find that the transition between the CO passivated and the reactive state is continuous if the concentration of the active sites is small, and it becomes discontinuous with increasing concentrations of active sites. Furthermore, it is shown that a hysteresis loop exists whether the CO-passivated transition is continuous or discontinuous. Our simulation results are in good agreement with many relevant experimental results and may provide an alternative explanation for the experimental observations.

Journal Article↗
PubMed1998

Mechanism and evolution of protein dimerization.

We have investigated the mechanism and the evolutionary pathway of protein dimerization through analysis of experimental structures of dimers. We propose that the evolution of dimers may have multiple pathways, including (1) formation of a functional dimer directly without going through an ancestor monomer, (2) formation of a stable monomer as an intermediate followed by mutations of its surface residues, and (3), a domain swapping mechanism, replacing one segment in a monomer by an equivalent segment from an identical chain in the dimer. Some of the dimers which are governed by a domain swapping mechanism may have evolved at an earlier stage of evolution via the second mechanism. Here, we follow the theory that the kinetic pathway reflects the evolutionary pathway. We analyze the structure-kinetics-evolution relationship for a collection of symmetric homodimers classified into three groups: (1) 14 dimers, which were referred to as domain swapping dimers in the literature; (2) nine 2-state dimers, which have no measurable intermediates in equilibrium denaturation; and (3), eight 3-state dimers, which have stable intermediates in equilibrium denaturation. The analysis consists of the following stages: (i) The dimer is divided into two structural units, which have twofold symmetry. Each unit contains a contiguous segment from one polypeptide chain of the dimer, and its complementary contiguous segment from the other chain. (ii) The division is repeated progressively, with different combinations of the two segments in each unit. (iii) The coefficient of compactness is calculated for the units in all divisions. The coefficients obtained for different cuttings of a dimer form a compactness profile. The profile probes the structural organization of the two chains in a dimer and the stability of the monomeric state. We describe the features of the compactness profiles in each of the three dimer groups. The profiles identify the swapping segments in domain swapping dimers, and can usually predict whether a dimer has domain swapping. The kinetics of dimerization indicates that some dimers which have been assigned in the literature as domain swapping cases, dimerize through the 2-state kinetics, rather than through swapping segments of performed monomers. The compactness profiles indicate a wide spectrum in the kinetics of dimerization: dimers having no intermediate stable monomers; dimers having an intermediate with a stable monomer structure; and dimers having an intermediate with a stable structure in part of the monomer. These correspond to the multiple evolutionary pathways for dimer formation. The evolutionary mechanisms proposed here for dimers are applicable to other oligomers as well.

Biological Evolution↗
PubMed1999

D-dimer testing in the diagnosis of acute venous thromboembolism.

Patients with acute VTE require clinical assessment and objective testing to be accurately diagnosed. Almost all patients with acute VTE have an elevated D-dimer level. An elevated D-dimer is associated with many illnesses, and therefore, is not specific for VTE. D-dimer tests can have a high sensitivity, however, which is useful because a normal test excludes the diagnosis of VTE. D-dimer testing is most appropriate in the assessment of outpatients because the prevalence of disease and the likelihood of comorbid conditions are lower than in inpatient populations, making a test of exclusion particularly valuable. Accuracy studies using conventional ELISA assays have confirmed that a test with a high sensitivity can be used to exclude a diagnosis of VTE, but conventional ELISA testing is not practical. Studies of more practical D-dimer testing indicate that, for patients with suspected DVT or PE, the need for serial testing or further investigation can be reduced if normal results are obtained using assays with a high sensitivity. There are, however, many sources of variation in the test characteristics of D-dimer assays. Therefore there is no reassurance that results from one manufacturer's test are applicable to other tests and different investigators may obtain varied results when using the same manufacturer's product. In addition, the results of D-dimer accuracy studies lack generalizability. This lack of generalizability has led to the recommendation that clinicians await the results of management studies before adopting the routine use of D-dimer assays in the diagnosis of VTE. Further, it may be reasonable to perform an accuracy study when planning to adopt a specific D-dimer assay from a published management trial, to be confident of its characteristics can be reproduced. In the management of patients with suspected DVT, rapid ELISA tests show promise as a practical D-dimer test, in that they have a sensitivity similar to that of the conventional ELISA assay. Two management studies have recently confirmed that a normal D-dimer result (using the SimpliRED whole-blood assay or the Instant IA rapid ELISA) in combination with a noninvasive test or a clinical model can reliably exclude DVT in outpatients. Use of a clinical model can reduce the need for VU, and the combination of a clinical model and D-dimer testing could further reduce the number of VU procedures required. As noted by Wells et al, who recently published a clinical model, however, a normal D-dimer result was most accurate in the patients with a low pretest likelihood (NPV = 99.5%) and least accurate in patients with a high pretest likelihood (NPV = 85.7%) Patients with a low pretest likelihood and a normal D-dimer are the largest proportion of outpatients referred for testing, and considerable resources may be saved if additional management studies confirm the usefulness of D-dimer testing in such patients. In patients with suspected PE, there is a lack of published management trials despite a number of accuracy studies indicating that D-dimer testing may be useful as a method of PE diagnosis exclusion. Recent results, however, from an accuracy study of patients with suspected PE who had D-dimer testing complement the findings of Wells et al in patients with suspected DVT. Using a standardized clinical model of PE in combination with a SimpliRED D-dimer assay, Ginsberg and colleagues found that the combination of a low pretest likelihood and a normal D-dimer had a negative predictive value of 99%, whereas the negative predictive value was only 78% in patients with a high pretest likelihood and a normal D-dimer. Similar to the findings in DVT, these results indicate that D-dimer testing is most useful in patients with a low pretest likelihood for PE and raise the possibility that such patients may not require lung scans. This finding is currently being evaluated in a prospective management trial.

Acute Disease↗
PubMed1999

Stability of the dimerization domain effects the cooperative DNA binding of short peptides.

The basic region peptide derived from the basic leucine zipper protein GCN4 bound specifically to the native GCN4 binding sequences in a dimeric form when the beta-cyclodextrin/adamantane dimerization domain was introduced at the C-terminus of the GCN4 basic region peptide. We describe here how the structure and stability of the dimerization domain affect the cooperative formation of the peptide dimer-DNA complex. The basic region peptides with five different guest molecules were synthesized, and their equilibrium dissociation constants with a peptide possessing beta-cyclodextrin were determined. These values, ranging from 1.3 to 15 microM, were used to estimate the stability of the complexes between the dimers with various guest/cyclodextrin dimerization domains and GCN4 target sequences. An efficient cooperative formation of the dimer complexes at the GCN4 binding sequence was observed when the adamantyl group was replaced with the norbornyl or noradamantyl group, but not with the cyclohexyl group that formed a beta-cyclodextrin complex with a stability that was 1 order of magnitude lower than that of the adamantyl group. Thus, cooperative formation of the stable dimer-DNA complex appeared to be effected by the stability of the dimerization domain. For the peptides that cooperatively formed dimer-DNA complexes, there was no linear correlation between the stability of the inclusion complex and that of the dimer-DNA complex. With the beta-cyclodextrin/adamantane dimerization domain, the basic region peptide dimer preferred to bind to a palindromic 5'-ATGACGTCAT-3' sequence over the sequence lacking the central G.C base pair and that with an additional G.C base pair in the middle. Changing the adamantyl group into a norbornyl group did not alter the preferential binding of the peptide dimers to the palindromic sequence, but slightly affected the selectivity of the dimer for other nonpalindromic sequences. The helical contents of the peptides in the DNA-bound dimer with the adamantyl group were decreased by reducing the stability of the dimer-DNA complex, which was possibly caused by deformation of the helical structure proximal to the dimerization domain.

Basic-Leucine Zipper Transcription Factors↗
PubMed2003

Elements located upstream and downstream of the major splice donor site influence the ability of HIV-2 leader RNA to dimerize in vitro.

An essential step in the replication cycle of all retroviruses is the dimerization of genomic RNA prior to or during budding and maturation of the viral particle. In HIV-1, a 5' leader region site termed stem-loop 1 (SL1) promotes RNA dimerization in vitro and influences dimerization in vivo. In HIV-2, two sequences promote dimerization of RNA fragments in vitro: the 5'-end of the primer-binding site (PBS) and a stem-loop region homologous to the HIV-1 SL1 sequence. Because HIV-2 RNA constructs of different lengths use these two dimerization signals disproportionately, we hypothesized that other sequences could modulate their relative utilization. Here, we characterized the influence of sequences upstream and downstream of the major splice donor site on the formation of HIV-2 RNA dimers in vitro using a variety of RNA constructs and dimerization and electrophoresis protocols. We first assayed the formation of loose or tight dimers for 1-444 and 1-561 model RNAs. Although both RNAs could form PBS-dependent loose dimers, the 1-561 RNA was unable to make SL1-dependent tight dimers. Using RNAs truncated at their 5'- and/or 3'-ends and by making compensatory base substitutions, we found that two elements interfere with the formation of SL1-dependent tight dimers. The cores of these elements are located at nucleotides 189-196 and 543-550. Our results suggest that base pairing between these sequences prevents the formation of SL1-dependent tight dimers, probably by sequestering SL1 in a stable intramolecular arrangement. Moreover, we found that nucleotides downstream of SL1 decreased the rate of tight dimerization. Interestingly, dimerization at 37 degrees C in the presence of nucleocapsid protein increased the yield of SL1-mediated tight dimerization in vitro, even in the presence of the two interfering elements, suggesting a relationship between the nucleocapsid protein and activation of the SL1 dimerization signal in vivo.

3' Untranslated Regions↗
PubMed2001

Ultrastructure and function of dimeric, soluble intercellular adhesion molecule-1 (ICAM-1).

Previous studies have demonstrated dimerization of intercellular adhesion molecule-1 (ICAM-1) on the cell surface and suggested a role for immunoglobulin superfamily domain 5 and/or the transmembrane domain in mediating such dimerization. Crystallization studies suggest that domain 1 may also mediate dimerization. ICAM-1 binds through domain 1 to the I domain of the integrin alpha(L)beta(2) (lymphocyte function-associated antigen 1). Soluble C-terminally dimerized ICAM-1 was made by replacing the transmembrane and cytoplasmic domains with an alpha-helical coiled coil. Electron microscopy revealed C-terminal dimers that were straight, slightly bent, and sometimes U-shaped. A small number of apparently closed ring-like dimers and W-shaped tetramers were found. To capture ICAM-1 dimerized at the crystallographically defined dimer interface in domain 1, cysteines were introduced into this interface. Several of these mutations resulted in the formation of soluble disulfide-bonded ICAM-1 dimers (domain 1 dimers). Combining a domain 1 cysteine mutation with the C-terminal dimers (domain 1/C-terminal dimers) resulted in significant amounts of both closed ring-like dimers and W-shaped tetramers. Surface plasmon resonance studies showed that all of the dimeric forms of ICAM-1 (domain 1, C-terminal, and domain 1/C-terminal dimers) bound similarly to the integrin alpha(L)beta(2) I domain, with affinities approximately 1.5--3-fold greater than that of monomeric ICAM-1. These studies demonstrate that ICAM-1 can form at least three different topologies and that dimerization at domain 1 does not interfere with binding in domain 1 to alpha(L)beta(2).

Amino Acid Substitution↗
PubMed1994

Analytical study of rat retrotransposon VL30 RNA dimerization in vitro and packaging in murine leukemia virus.

A sequence of the rat retrotransposon virus-like 30 S RNA (VL30) located next to the 5' end of the Harvey murine sarcoma virus (HaMSV) genome was recently found to form stable dimeric RNA in vitro and to direct the efficient packaging of VL30-derived recombinant RNAs into MuLV virions. To study the structure-function relationships of the rat VL30 dimerization-encapsidation signal (E/DLS), we have performed biochemical and genetic studies of rat VL30 RNA dimerization in vitro. The results show that temperature and specific cation/RNA interactions are important for VL30 dimerization in vitro. VL30 RNA dimerization is optimal at 55 degrees C and Li+ dramatically enhances the stability of VL30 dimeric RNA. In addition, a genetic analysis of VL30 RNA dimerization reveals that a 5' G-rich sequence is critical for dimer formation and that a UGUCUUGUC repeat contributes to VL30 dimer stability. Interestingly enough, substitution of an A for a G in the 5' G-rich sequence is sufficient to abolish VL30 RNA dimerization in vitro. Taken together, these biochemical and genetic data indicate that dimerization of VL30 RNA involves non-canonical base-pairings and possible purine-purine interactions. Nucleocapsid protein NCp10 of murine leukemia virus (MuLV), a gag-encoded protein that is tightly associated with genomic RNA in the virion core, has been shown to have nucleic acid binding and annealing activities. Here we report that the viral NCp10 protein is able to bind tightly to annealing activities. Here we report that the viral NCp10 protein is able to bind tightly to the retrotransposon VL30 RNA and to activate its dimerization. Moreover, mutations in the 5' G-rich sequence of the VL30 dimerization sequence impaired NCp10 binding to RNA. Recombinant MLV-VL30 vectors with mutations in the VL30 dimerization sequence were constructed. Results obtained in vivo clearly show that the mutations that had a deleterious effect on the packaging of MLV-VL30 retroviral vector in vivo were those that impaired VL30 RNA dimerization and interactions with NCp10 in vitro, even the single mutation in the 5' G-rich region. Therefore, these findings suggest that packaging of VL30 RNA into MuLV virions requires specific interactions between RNA dimerization sequences and viral NC protein molecules.

3T3 Cells↗
PubMed1994

A 19-nucleotide sequence upstream of the 5' major splice donor is part of the dimerization domain of human immunodeficiency virus 1 genomic RNA.

The genome of all retroviruses, including human immunodeficiency virus type 1 (HIV-1), consists of two identical RNAs noncovalently linked near their 5' end. Dimerization of genomic RNA is thought to modulate several steps in the retroviral life cycle, such as recombination, translation, and encapsidation. We report the results of experiments designed to identify the 5' and 3' boundaries of the dimerization domain of the HIV-1 genome: (1) An HIV-1 RNA starting at nucleotide 252 or at other downstream positions (four tested) does not dimerize despite the inclusion of the whole of a previously proposed dimerization domain (nucleotides 295-401); (2) an RNA starting between nucleotides 242 and 249 (five positions tested) dimerizes to a variable extent depending on the starting position; (3) an RNA starting at nucleotide 233 or at other upstream positions (five tested) is fully or > 80% dimeric; (4) an RNA starting at nucleotide 1 but lacking the 233-251 or the 242-251 region is, respectively, fully monomeric or about 50% monomeric; (5) the 343-401 region contains two strings of G's (GGGGG367 and GGG384) that had been postulated to promote genome dimerization through the formation of guanine quartets. We have deleted the 379-401, 358-401, and 343-401 regions from otherwise dimeric RNAs without changing their ability to dimerize. We reach three conclusions: (1) a dimerization signal exists upstream of the major 5' splice donor (nucleotide 290); (2) the previously proposed downstream dimerization domain is insufficient to promote dimerization and has a 3' half that is not necessary to obtain fully dimeric RNAs; (3) the 5' boundary of the HIV-1 dimerization domain is located somewhere between nucleotides 233 and 242, and the 3' boundary is located no farther than at nucleotide 342, making it possible that the 5' and 3' boundaries of the HIV-1 dimerization domain are both located within the leader sequence. We speculate that the 248-270 or 233-285 region forms a hairpin that is the core dimerization domain of HIV-1 RNA.

Base Sequence↗
PubMed2003

Comparison of six D-dimer methods in patients suspected of deep vein thrombosis.

We evaluated six D-dimer methods to determine their sensitivity, specificity, and negative predictive values (NPV) in symptomatic patients suspected of deep vein thrombosis (DVT). In patients suspected of DVT a whole blood D-dimer test (SimpliRED, Agen) was performed, and then tested using enzyme-linked immunosorbent assay (VIDAS D-Dimer, BioMerieux; Asserachrome D-Di, Stago International; Dimertest Gold, Agen) and automated immunoturbidometric methods (Advanced D-Dimer, Dade Behring; MiniQuant, Biopool). Each D-dimer method was independently compared with radiographic results to determine sensitivity and NPV. There were 151 patients enrolled in the study. Thirty-five (23.2%) patients had a positive Doppler ultrasound, with 26 proximal, eight distal, and one patient with both proximal and distal thrombus. Two patients (1.3%) had inconclusive studies and were excluded from the analyses. For all patients, the sensitivities for the rapid D-dimer methods were: SimpliRED, 82.3% [95% confidence interval (CI), 80.3-84.3%]; VIDAS D-Dimer, 91.4% (95% CI, 89.9-92.9%); MiniQuant D-Dimer, 96.3% (95% CI, 95.1-97.5%); and Advanced D-Dimer, 97.1% (95% CI, 96.3-97.9%). The sensitivity improved for SimpliRED (86.4%; 95% CI, 83.3-89.4%), VIDAS D-Dimer (95.5%; 95% CI, 85.0-100%), MiniQuant D-Dimer (100%; 95% CI, 96.9-100%) and Advanced D-Dimer (100%; 95% CI, 98.9-100%) in the inpatient population. The automated immunoturbidometric methods, the MiniQuant D-Dimer and Advanced D-Dimer, demonstrated comparable sensitivities and NPV with the VIDAS D-Dimer method in symptomatic patients suspected of DVT, which would suggest that these newer D-dimer methods could be used as part of the diagnostic algorithm for patients suspected of DVT.

Enzyme-Linked Immunosorbent Assay↗