Preface to COAST 2016 innovators' workshop on personalized and precision orthodontic therapy.

OBJECTIVE: A second focused workshop explored how to transfer novel findings into clinical orthodontic practice. SETTING AND SAMPLE POPULATION: Participants met in West Palm Beach (Florida, USA), on 9-11 September 2016 for the Consortium for Orthodontic Advances in Science and Technology 2016 Innovators' Workshop (COAST). Approximately 65 registered attendees considered and discussed information from 27 to 34 speakers, 8 to 15 poster presenters and four lunch-hour focus group leaders. MATERIAL AND METHODS: The innovators' workshops were organized according to five themed sessions. The aims of the discussion sessions were to identify the following: i) the strength and impact of the evidenced-based discoveries, ii) required steps to enable further development and iii) required steps to translate these new discoveries into orthodontic practice. RESULTS: The role of gene-environment interactions that underlie complex craniofacial traits was the focus of several sessions. It was agreed that diverse approaches are called for, such as (i) large-scale collaborative efforts for future genetic studies of complex traits; (ii) deep genome sequencing to address the issues of isolated mutations; (iii) quantifying epigenetic-environmental variables in diverse areas myofascial pain, alveolar remodelling and mandibular growth. Common needs identified from the themed sessions were multiscale/multispecies modelling and experimentation using controlled and quantified mechanics and translation of the findings in bone biology between species. Panel discussions led to the consensus that a consortium approach to establish standards for intra-oral scanning and 3D imaging should be initiated. CONCLUSIONS: Current and emerging technologies still require supported research to translate new findings from the laboratory to orthodontic practice.

Novel conformation-selective alpha-synuclein antibodies raised against different in vitro fibril forms show distinct patterns of Lewy pathology in Parkinson's disease.

AIMS: The aim of this study was to test the hypothesis that different conformations of misfolded α-synuclein (α-syn) are present in Parkinson's disease (PD) brain. METHODS: Using two previously characterized conformations of α-syn fibrils, we generated new conformation-selective α-syn monoclonal antibodies (mAbs). We then interrogated multiple brain regions in a well-characterized autopsy cohort of PD patients (n = 49) with these mAbs, Syn7015 and Syn9029. RESULTS: Syn7015 detects Lewy bodies (LBs) and Lewy neurites (LNs) formed by pathological α-syn in all brain regions tested, and is particularly sensitive to LNs and small Lewy dots, inclusions believed to form early in the disease. Further, we observed colocalization between Syn7015 and an early marker of α-syn pathology formation, phospho-Ser129-α-syn, and a lack of extensive colocalization with markers of more mature pathology. In comparison, Syn9029 detects Lewy pathology in all regions examined, but indicates significantly fewer LNs than Syn7015. In addition, colocalization of Syn9029 with later markers of α-syn pathology maturation (ubiquitin and P62) suggests that the pathology detected by Syn9029 is older. Semiquantitative scoring of both LN and LB pathology in nine brain regions further established this trend, with Syn7015 LN scores consistently higher than Syn9029 LN scores. CONCLUSIONS: Our data indicate that different conformations of α-syn pathology are present in PD brain and correspond to different stages of maturity for Lewy pathology. Regional analysis of Syn7015 and Syn9029 immunostaining also provides support for the Braak hypothesis that α-syn pathology advances through the brain.

Operative Treatment of Traumatic Hallux Valgus in Elite Athletes.

BACKGROUND: Traumatic hallux valgus is an increasingly common injury in the athletic population and represents a unique variant of turf toe. Failure to appropriately recognize and treat these injuries can lead to continued pain, decreased performance, progressive deformities, and ultimately degeneration of the hallux metatarsophalangeal joint. Limited literature currently exists to assist in the diagnosis, management, and operative treatment. METHODS: Nineteen patients were reviewed in this series, including 12 National Football League, 6 college, and 1 high school player who was a college prospect. The average age for all patients at the time of surgery was 24.4 years (range, 19-33 years). Return to play and complications were evaluated. RESULTS: Overall, good operative results were obtained, with 74% of patients returning to their preinjury level of play at an average recovery time of 3.4 months. CONCLUSION: Traumatic hallux valgus is an increasingly common injury in the athletic population and represents a unique variant of turf toe. The impact of this injury cannot be overstated, as one-quarter of players were unable to return to play. LEVEL OF EVIDENCE: Level IV, case series.

Personalized and precision orthodontic therapy.

OBJECTIVE: To bring together orthodontic stakeholders from academics, industry, and private practice for a series of thematically focused workshops to explore and develop the transfer of novel approaches into clinical orthodontic practice. SETTING AND SAMPLE POPULATION: Twenty-seven invited speakers, eight poster presenters, and participants of the Consortium for Orthodontic Advances in Science and Technology (COAST) 2014 Innovators' Workshop at the Eaglewood Resort and Spa, Itasca, Illinois, September 11-14, 2014. MATERIAL AND METHODS: Five themed sessions involving between 4-7 presentations followed by panel discussions were organized. The aims of the discussion sessions were to highlight important findings and consider the strength of evidence for these, indicate next steps and needed research or technological developments to move forward, and to weigh the expected benefits from these findings and steps to implement in clinical practice. RESULTS: Among important areas for attention identified were need for multiscale and multispecies modeling and experimentation for interspecies translation of results; large-scale collaborative efforts within the profession to address the need for adequate sample sizes for future genetic studies of complex traits such as malocclusion; a consortium approach to improve new technologies such as intra-oral scanning and 3D imaging by establishing standards; and harnessing the growing body of knowledge about bone biology for application in orthodontics. CONCLUSIONS: With increased awareness of the potential of current and emerging technologies, translation of personalized and precision approaches in the field of orthodontics holds ever-increasing promise.

Accuracy of alveolar bone measurements from cone beam computed tomography acquired using varying settings.

OBJECTIVES: To investigate the accuracy and reliability of cone beam computed tomography (CBCT) measurements of buccal alveolar bone height (BBH) and thickness (BBT) using custom acquisition settings. SETTINGS AND SAMPLE POPULATION: School of Dentistry, Oregon Health & Science University. Twelve embalmed cadavers. MATERIALS AND METHODS: Cadaver heads were imaged by CBCT (i-CAT® 17-19, Imaging Sciences International, Hatfield, PA) using a 'long scan' (LS) setting with 619 projection images, 360° revolution, 26.9 s duration, and 0.2 mm voxel size, and using a 'short scan' (SS) setting with 169 projection images, 180° rotation, 4.8 s duration, and 0.3 mm voxel size. BBH and BBT were measured with 65 teeth, indirectly from CBCT images and directly through dissection. Comparisons were assessed using paired t-tests (p≤0.05). Level of agreement was assessed by concordance correlation coefficients, Pearson's correlation coefficients, and Bland-Altman plots. RESULTS: Mean differences in measurements compared to direct measurements were as follows, LS 0.17±0.12 (BBH) and 0.10±0.07 mm (BBT), and SS 0.41±0.32 (BBH) and 0.12±0.11 mm (BBT). No statistical differences were found with any of BBH or BBT measurements. Correlation coefficients and Bland-Altman plots showed agreement was high between direct and indirect measurement methods, although agreement was stronger for measurements of BBH than BBT. CONCLUSIONS: Compared to the LS, the similarity in results with the reduced scan times and hence reduced effective radiation dose, favors use of shorter scans, unless other purposes for higher resolution imaging can be defined.

Cartilage lesions in patellofemoral dislocations: incidents/locations/when to treat.

Patellofemoral (PF) dislocations are frequently associated with chondral injury. Chondral and osteochondral lesions are often associated with traumatic (high-energy) PF dislocations, whereas atraumatic (low-energy) PF dislocations in patients with significant PF risk factors have a much lower incidence of osteochondral damage. This article provides a historical overview and delineates the current state of radiographic and clinical outcomes of osteochondral lesions after PF dislocation. The importance of understanding risk factors of redislocation is emphasized, and the current treatment options for these cartilage lesions associated with PF dislocation are briefly summarized.

Human experience seeking correlates with hippocampus volume: convergent evidence from manual tracing and voxel-based morphometry.

Experience seekers continuously pursue novel environmental stimuli, a tendency linked to genetic variation in mesolimbic dopamine transmission. However, the neuroanatomical basis accompanying these genetic and neurochemical associations is unknown. Animal and human experimental results suggest a central role for the hippocampus in processing novel stimuli. Here, we explored whether differences in human experience seeking are related to variations in hippocampal volume. High-resolution anatomic MR images were analyzed in 40 individuals who ranged from low through high on a validated experience seeking personality scale. Manual tracing analysis demonstrated positive correlation between right hippocampal volumes and scores on the experience seeking scale. A separate voxel-based morphometric analysis confirmed these results and localized the significant increase to the anterior portion of right hippocampal grey matter. We tested and were able to reject the possibility that results were mediated by a personality trait related to, but distinct from, experience seeking. The present data provide the first direct evidence for a relationship between human experience seeking and brain structure. In addition, these results provide new ecologically relevant evidence for a link between right anterior hippocampus and novelty processing.

Linking pathway gene expressions to the growth inhibition response from the National Cancer Institute's anticancer screen and drug mechanism of action.

Novel strategies are proposed to quantitatively analyze and relate biological pathways to drug responses using gene expression and small-molecule growth inhibition data (GI(50)) derived from the National Cancer Institute's 60 cancer cells (NCI(60)). We have annotated groups of drug GI(50) responses with pathways defined by the Kyoto Encyclopedia of Genes and Genomes (KEGG) and BioCarta, and functional categories defined by Gene Ontology (GO), through correlations between pathway gene expression patterns and drug GI(50) profiles. Drug-gene-pathway relationships may then be utilized to find drug targets or target-specific drugs. Significantly correlated pathways and the gene products involved represent interesting targets for further exploration, whereas drugs that are significantly correlated with only certain pathways are more likely to be target specific. Separate pathway clustering finds that pathways engaged in the same biological process tend to have similar drug correlation patterns. The biological and statistical significances of our method are established by comparison to known small-molecule inhibitor-gene target relationships reported in the literature and by standard randomization procedures. The results of our pathway, gene expression and drug-induced growth inhibition associations, can serve as a basis for proposing testable hypotheses about potential anticancer drugs, their targets, and mechanisms of action.

Molecular motions and conformational changes of HPPK.

6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) belongs to a class of catalytic enzymes involved in phosphoryl transfer and is a new target for the development of novel antimicrobial agents. In the present study, the fundamental consideration is to view the overall structure of HPPK as a network of interacting residues and to extract the most cooperative collective motions that define its global dynamics. A coarse-grained model, harmonically constrained according to HPPK's crystal structure is used. Four crystal structures of HPPK (one apo and three holo forms with different nucleotide and pterin analogs) are studied with the goal of providing insights about the function-dynamic correlation and ligand induced conformational changes. The dynamic differences are examined between HPPK's apo- and holo-forms, because they are involved in the catalytic reaction steps. Our results indicate that the palm-like structure of HPPK is nearly rigid, whereas the two flexible loops: L2 (residues 43-53) and L3 (residues 82-92) exhibit the most concerted motions for ligand recognition and presumably, catalysis. These two flexible loops are involved in the recognition of HPPKs nucleotide and pterin ligands, whereas the rigid palm region is associated with binding of these cognate ligands. Six domains of collective motions are identified, comprised of structurally close but not necessarily sequential residues. Two of these domains correspond to the flexible loops (L2 and L3), whereas the remaining domains correspond to the rigid part of the molecule.

Molecular mechanisms of chaperonin GroEL-GroES function.

The dynamics of the GroEL-GroES complex is investigated with a coarse-grained model. This model is one in which single-residue points are connected to other such points, which are nearby, by identical springs, forming a network of interactions. The nature of the most important (slowest) normal modes reveals a wide variety of motions uniquely dependent upon the central cavity of the structure, including opposed torsional rotation of the two GroEL rings accompanied by the alternating compression and expansion of the GroES cap binding region, bending, shear, opposed radial breathing of the cis and trans rings, and stretching and contraction along the protein assembly's long axis. The intermediate domains of the subunits are bifunctional due to the presence of two hinges, which are alternatively activated or frozen by an ATP-dependent mechanism. ATP binding stabilizes a relatively open conformation (with respect to the central cavity) and hinders the motion of the hinge site connecting the intermediate and equatorial domains, while enhancing the flexibility of the second hinge that sets in motion the apical domains. The relative flexibilities of the hinges are reversed in the nucleotide-free form. Cooperative cross-correlations between subunits provide information about the mechanism of action of the protein. The mechanical motions driven by the different modes provide variable binding surfaces and variable sized cavities in the interior to enable accommodation of a broad range of protein substrates. These modes of motion could be used to manipulate the substrate's conformations.

Reactivity of zinc finger cores: analysis of protein packing and electrostatic screening.

The chemical stability of 207 zinc fingers, derived from 92 experimental protein structures, is evaluated according to the protein packing and electrostatic screening of their zinc cores. These properties are used as measures of the protein protection of zinc cores, to predictively rank relative zinc finger reactivities and assess differences in function. On average, there is a substantial and concomitant increase in the screening of increasingly anionic core motifs, suggesting zinc fingers have evolved in a manner that promotes shielding of their potentially reactive core thiolates. In contrast, enzymatic zinc cores are functionally differentiated by negative electrostatic screening. Zinc finger cores are predominantly screened by networks of backbone:core NH-S hydrogen bonds that electronically stabilize core thiolates and enhance backbone packing. Stabilizing protein:core interactions can be mapped to conserved residues, including [Arg,Lys]:core salt-bridges in some protein families. Labile zinc fingers are identified by poorly screened cores, possibly indicating redox or metallothionein (MT) regulated function. Consistent with experiment, the cores of the C-terminal finger of the human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein p7 (NCp7) and Escherichia coli Ada protein (Ada) "finger" are identified as reactive. The C-terminal zinc fingers of nuclear receptors are predicted to be the most labile in this study, particularly the human estrogen receptor (hER), which contains a triad of reactive thiolates. We propose that hER DNA binding is redox and MT regulated through the C-terminal finger and that weak electrophilic agents may inhibit hER-mediated transcription, implicated in breast cancer progression.

Screening the molecular surface of human anticoagulant protein C: a search for interaction sites.

Protein C (PC), a 62 kDa multi-modular zymogen, is activated to an anticoagulant serine protease (activated PC or APC) by thrombin bound to thrombomodulin on the surface of endothelial cells. PC/APC interacts with many proteins and the characterisation of these interactions is not trivial. However, molecular modelling methods help to study these complex biological processes and provide basis for rational experimental design and interpretation of the results. PC/APC consists of a Gla domain followed by two EGF modules and a serine protease domain. In this report, we present two structural models for full-length APC and two equivalent models for full-length PC, based on the X-ray structures of Gla-domainless APC and of known serine protease zymogens. The overall elongated shape of the models is further cross-validated using size exclusion chromatography which allows evaluation of the Stokes radius (rs for PC = 33.15 A; rs for APC = 34.19 A), frictional ratio and axial ratio. We then propose potential binding sites at the surface of PC/APC using surface hydrophobicity as a determinant of the preferred sites of intermolecular recognition. Most of the predicted binding sites are consistent with previously reported experimental data, while some clusters highlight new regions that should be involved in protein-protein interactions.

Serologic survey for selected infectious disease agents in swift and kit foxes from the western United States.

A serologic survey of swift fox (Vulpes velox) and kit fox (V. macrotis) from the western USA was conducted for 12 infectious diseases. Samples from swift fox were collected between 1987 and 1992 from Colorado (n = 44), Kansas (n = 10), and Wyoming (n = 9). Samples from kit fox were collected in California (n = 86), New Mexico (n = 18), Utah (n = 9), and Arizona (n = 6). Overall antibody prevalence rates were 33 of 110 (30%) for canine parvovirus (CPV), 9 of 72 (13%) for canine distemper virus (CDV), 23 of 117 (20%) for vesicular stomatitis New Jersey, 16 of 117 (14%) for vesicular stomatitis Indiana, six of 117 (5%) for Cache Valley virus, five of 117 (4%) for Jamestown Canyon virus, one of 97 (1%) for rabies virus, one of 117 (1%) for Colorado tick fever virus, and one of 117 (1%) for western equine encephalitis virus. In addition, antibodies were not found to Yersinia pestis, Francisella tularensis, and Borrelia burgdorferi in serum from 25 Colorado swift fox. Adult swift fox from Colorado had serologic evidence of exposure to CPV more often than juveniles. No juvenile swift fox from Colorado had serum antibodies to CDV. There were season-specific differences in serum antibody prevalence for CPV for swift fox from Colorado. No viruses were isolated from ectoparasites or fox from Colorado.

Mapping the binding site of colchicinoids on beta -tubulin. 2-Chloroacetyl-2-demethylthiocolchicine covalently reacts predominantly with cysteine 239 and secondarily with cysteine 354.

2-Chloroacetyl-2-demethylthiocolchicine (2CTC) and 3-chloroacetyl-3-demethylthiocolchicine (3CTC) resemble colchicine in binding to tubulin and react covalently with beta-tubulin, forming adducts with cysteine residues 239 and 354. The adducts at Cys-239 are less stable than those at Cys-354 during formic acid digestion. Extrapolating to zero time, the Cys-239 to Cys-354 adduct ratio is 77:23 for 2CTC and 27:73 for 3CTC. Using energy minimization modeling to dock colchicinoids into the electron crystallographic model of beta-tubulin in protofilaments (Nogales, E. , Wolf, S. G., and Downing, K. H. (1998) Nature 391, 199-203), we found two potential binding sites. At one, entirely encompassed within beta-tubulin, the C2- and C3-oxygen atoms of 2CTC and 3CTC overlapped poorly with those of colchicine and thiocolchicine, but distances from the reactive carbon atoms of the analogs to the sulfur atoms of the cysteine residues were qualitatively consistent with reactivity. The other potential binding site was located at the alpha/beta interface. Here, the oxygen atoms of the analogs overlapped well with those of colchicine, but relative distances of the reactive carbons to the cysteine sulfur atoms did not correlate with the observed reactivity. A significant conformational change must occur in the colchicine binding site of tubulin in the transition from the unpolymerized to the polymerized state.

Characterization of anticancer agents by their growth inhibitory activity and relationships to mechanism of action and structure.

An analysis of the growth inhibitory potency of 122 anticancer agents available from the National Cancer Institute anticancer drug screen is presented. Methods of singular value decomposition (SVD) were applied to determine the matrix of distances between all compounds. These SVD-derived dissimilarity distances were used to cluster compounds that exhibit similar tumor growth inhibitory activity patterns against 60 human cancer cell lines. Cluster analysis divides the 122 standard agents into 25 statistically distinct groups. The first eight groups include structurally diverse compounds with reactive functionalities that act as DNA-damaging agents while the remaining 17 groups include compounds that inhibit nucleic acid biosynthesis and mitosis. Examination of the average activity patterns across the 60 tumor cell lines reveals unique 'fingerprints' associated with each group. A diverse set of structural features are observed for compounds within these groups, with frequent occurrences of strong within-group structural similarities. Clustering of cell types by their response to the 122 anticancer agents divides the 60 cell types into 21 groups. The strongest within-panel groupings were found for the renal, leukemia and ovarian cell panels. These results contribute to the basis for comparisons between log(GI(50)) screening patterns of the 122 anticancer agents and additional tested compounds.

Relating the Structure of HIV-1 Reverse Transcriptase to Its Processing Step.

Abstract By treating an enzyme as a coarse-grained uniform block of material, utilizing only the α-Carbon positions, the normal modes of motion can be obtained. For reverse transcriptase the slower of these motions are suggestive of being involved in the processing step, where the RNA or DNA strand is copied onto a new DNA strand at a polymerase site, and the RNA strand is subsequently cut up at the distant Ribonuclease H site. The slowest mode of motion involves hinge bending about a site midway between the polymerase and Ribonuclease H sites, suggesting that it can push or pull the RNA strand between these two sites. Pulling the nucleic acid strand would require tight binding to the RNase H site. The next slowest mode involves a hinge that opens and closes the protein like a clamp, which could facilitate the release of the nucleic acids for their step-wise progression. The third mode could rotate the substrate. An overall description of the step-wise processing step would involve close coordination among these steps. Results suggest that the smaller p51 subunit serves only as ballast to support the various modes of motion involving the different parts of the p66 subunit.

A cephalometric study of class II Division 1 malocclusions treated with the Jasper Jumper appliance.

This lateral cephalometric study investigated the dental and skeletal effects of the Jasper Jumper appliance used in the correction of Class II Division 1 malocclusions. A sample of 36 growing patients treated with the Jasper Jumper appliance was divided into two groups: (1) 24 patients with records obtained at the start and completion of orthodontic treatment, and (2) 12 patients with records available at the beginning and end of the Jumper phase of treatment. Treatment effects were determined by statistical comparisons of cephalometric changes in the patients relative to age-adjusted cephalometric standards, and from structural superimpositions. While the Jumpers were in place, maxillary incisors were retroclined and the molars were moved distally, tipped back, and intruded. The mandibular incisors were proclined and intruded, while the molars were translated mesially, tipped forward, and extruded. Skeletal measures showed reduced forward maxillary displacement and no significant alteration of horizontal mandibular growth. During orthodontic finishing, molar tipping and maxillary incisor retroclination were corrected, although the mandibular incisors remained proclined. In summary, this study found that the Jasper Jumper appliance corrected Class II discrepancies largely through maxillary and mandibular dentoalveolar effects and, to a limited extent, by restraint of forward maxillary growth.

Cooperative folding units of escherichia coli tryptophan repressor.

A previously published computational procedure was used to identify cooperative folding units within tryptophan repressor. The theoretical results predict the existence of distinct stable substructures in the protein chain for the monomer and the dimer. The predictions were compared with experimental data on structure and folding of the repressor and its proteolytic fragments and show excellent agreement for the dimeric form of the protein. The results suggest that the monomer, the structure of which is currently unknown, is likely to have a structure different from the one it has within the context of the highly intertwined dimer. Application of this method to the repressor monomer represents an extension of the computations into the realm of evaluating hypothetical structures such as those produced by threading.

Synthesis and biological properties of novel pyridinioalkanoyl thiolesters (PATE) as anti-HIV-1 agents that target the viral nucleocapsid protein zinc fingers.

Nucleocapsid p7 protein (NCp7) zinc finger domains of the human immunodeficiency virus type 1 (HIV-1) are being developed as antiviral targets due to their key roles in viral replication and their mutationally nonpermissive nature. On the basis of our experience with symmetrical disulfide benzamides (DIBAs; Rice et al. Science 1995, 270, 1194-1197), we synthesized and evaluated variants of these dimers, including sets of 4,4'- and 3,3'-disubstituted diphenyl sulfones and their monomeric benzisothiazolone derivatives (BITA). BITAs generally exhibited diminished antiviral potency when compared to their disulfide precursors. Novel, monomeric structures were created by linking haloalkanoyl groups to the benzamide ring through -NH-C(=O)- (amide) or -S-C(=O)- (thiolester) bridges. Amide-linked compounds generally lacked antiviral activity, while haloalkanoyl thiolesters and non-halogen-bearing analogues frequently exhibited acceptable antiviral potency, thus establishing thiolester benzamides per se as a new anti-HIV chemotype. Pyridinioalkanoyl thiolesters (PATEs) exhibited superior anti-HIV-1 activity with minimal cellular toxicity and appreciable water solubility. PATEs were shown to preferentially target the NCp7 Zn finger when tested against other molecular targets, thus identifying thiolester benzamides, and PATEs in particular, as novel NCp7 Zn finger inhibitors for in vivo studies.

Collective motions in HIV-1 reverse transcriptase: examination of flexibility and enzyme function.

In order to study the inferences of structure for mechanism, the collective motions of the retroviral reverse transcriptase HIV-1 RT (RT) are examined using the Gaussian network model (GNM) of proteins. This model is particularly suitable for elucidating the global dynamic characteristics of large proteins such as the presently investigated heterodimeric RT comprising a total of 982 residues. Local packing density and coordination order of amino acid residues is inspected by the GNM to determine the type and range of motions, both at the residue level and on a global scale, such as the correlated movements of entire subdomains. Of the two subunits, p66 and p51, forming the RT, only p66 has a DNA-binding cleft and a functional polymerase active site. This difference in the structure of the two subunits is shown here to be reflected in their dynamic characteristics: only p66 has the potential to undergo large-scale cooperative motions in the heterodimer, while p51 is essentially rigid. Taken together, the global motion of the RT heterodimer is comprised of movements of the p66 thumb subdomain perpendicular to those of the p66 fingers, accompanied by anticorrelated fluctuations of the RNase H domain and p51 thumb, thus providing information about the details of one processivity mechanism. A few clusters of residues, generally distant in sequence but close in space, are identified in the p66 palm and connection subdomains, which form the hinge-bending regions that control the highly concerted motion of the subdomains. These regions include the catalytically active site and the non-nucleoside inhibitor binding pocket of p66 polymerase, as well as sites whose mutations have been shown to impair enzyme activity. It is easily conceivable that this hinge region, indicated by GNM analysis to play a critical role in modulating the global motion, is locked into an inactive conformation upon binding of an inhibitor. Comparative analysis of the dynamic characteristics of the unliganded and liganded dimers indicates severe repression of the mobility of the p66 thumb in RT's global mode, upon binding of non-nucleoside inhibitors.