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PubMed1998

ATP analogs and muscle contraction: mechanics and kinetics of nucleoside triphosphate binding and hydrolysis.

The mechanical behavior of skinned rabbit psoas muscle fiber contractions and in vitro motility of F-actin (Vf) have been examined using ATP, CTP, UTP, or their 2-deoxy forms (collectively designated as nucleotide triphosphates or NTPs) as contractile substrates. Measurements of actin-activated heavy meromyosin (HMM) NTPase, the rates of NTP binding to myosin and actomyosin, NTP-mediated acto-HMM dissociation, and NTP hydrolysis by acto-HMM were made for comparison to the mechanical results. The data suggest a very similar mechanism of acto-HMM NTP hydrolysis. Whereas all NTPs studied support force production and stiffness that vary by a factor 2 or less, the unloaded shortening velocity (Vu) of muscle fibers varies by almost 10-fold. 2-Deoxy ATP (dATP) was unique in that Vu was 30% greater than with ATP. Parallel behavior was observed between Vf and the steady-state maximum actin-activated HMM ATPase rate. Further comparisons suggest that the variation in force correlates with the rate and equilibrium constant for NTP cleavage; the variations in Vu or Vf are related to the rate of cross-bridge dissociation caused by NTP binding or to the rate(s) of product release.

Acid Anhydride Hydrolases↗
PubMed1999

Effects of SH1 and SH2 modifications on myosin: similarities and differences.

The properties of myosin modified at the SH2 group (Cys-697) were studied and compared with the previously reported properties of myosin modified at the SH1 group (Cys-707). 4-[N-[(iodoacetoxy)ethyl]-N methylamino]-7-nitrobenz-2-oxa-1, 3-diazole (IANBD) was used for selective modification of the SH2 group on myosin. SH2-labeled heavy meromyosin (SH2-HMM), similar to SH1-labeled HMM (SH1-HMM), did not propel actin filaments in the in vitro motility assays. SH1- and SH2-HMM produced similar amounts of load in the mixtures with unmodified HMM; the sliding speed of actin filaments gradually decreased with an increase in the fraction of either one of the modified HMMs in the mixture. In analogy to SH1-labeled myosin subfragment 1 (SH1-S1), SH2-labeled S1 (SH2-S1) activated regulated actin in the in vitro motility assays. SH2 modification inhibited Mg-ATPase of S1 and its activation by actin. The weak binding of S1 to actin was unaffected whereas the strong binding was weakened by SH2 modification. Overall, our results demonstrate similar behavior of SH1- and SH2-modified myosin heads in the in vitro motility assays despite some differences in their enzymatic properties. The effects of these modifications are ascribed to the location of the SH1-SH2 helix relative to other functional centers of S1.

Actins↗
PubMed1997

The possible role of myosin A1 light chain in the weakening of actin-myosin interaction.

The effects resulting from the removal of the N-terminus of myosin A1 by limited papain cleavage are investigated. The myosin and heavy meromyosin K+-ATPase and Ca2+-ATPase activities, and actin-activated ATPase activity of heavy meromyosin (HMM) and subfragment-1, are studied. Myosin and HMM preparations devoid of the A1 N-terminus exhibits lower Ca2+-ATPase activities at low ionic strength whereas no differences in K+- or Ca2+-ATPase activities are observed at high ionic strength. Direct binding of actin to monomeric myosin under K+-activated ATPase conditions is much more effective for myosin containing a shortened A1 light chain. The kinetic constants K(app) for actin and V(max) are calculated from actin-activation curves for HMM and subfragment-1. The kinetic constants for HMM are determined under conditions assuring saturation of regulatory light chains (RLC) either with Mg2+ or Ca2+. The removal of the A1 N-terminus influences the actin-myosin interaction in a Ca2+- and phosphorylation-dependent manner; in most cases, this leads to an increase in affinity. In the case of subfragment-1, the removal of the N-terminus of A1 led to a decrease in affinity. It is reasonable to assume that the intact A1 light chain may cause weakening of the actin-myosin interaction under certain conditions. This weakening may be regulated by RLC phosphorylation and RLC-bound calcium-for-magnesium exchange. Such an effect requires a structural minimum that is present in HMM but not in subfragment-1. Implications of such a role for the A1 N-terminus in the myosin-actin interaction are discussed.

Actins↗
PubMed1991

Mechanism for the inhibition of acto-heavy meromyosin ATPase by the actin/calmodulin binding domain of caldesmon.

Caldesmon, an actin/calmodulin binding protein, inhibits acto-heavy meromyosin (HMM) ATPase, while it increases the binding of HMM to actin, presumably mediated through an interaction between the myosin subfragment 2 region of HMM and caldesmon, which is bound to actin. In order to study the mechanism for the inhibition of acto-HM ATPase, we utilized the chymotryptic fragment of caldesmon (38-kDa fragment), which possesses the actin/calmodulin binding region but lacks the myosin binding portion. The 38-kDa fragment inhibits the actin-activated HMM ATPase to the same extent as does the intact caldesmon molecule. In the absence of tropomyosin, the 38-kDa fragment decreased the KATPase and Kbinding without any effect on the Vmax. However, when the actin filament contained bound tropomyosin, the caldesmon fragment caused a 2-3-fold decrease in the Vmax, in addition to lowering the KATPase and the Kbinding. The 38-kDa fragment-induced inhibition is partially reversed by calmodulin at a 10:1 molar ratio to caldesmon fragment; the reversal was more remarkable in 100 mM ionic strength at 37 degrees C than in 20 or 50 mM at 25 degrees C. Results from these experiments demonstrate that the 38-kDa domain of caldesmon fragment of myosin head to actin; however, when the actin filament contains bound tropomyosin, caldesmon fragment affects not only the binding of HMM to/actin but also the catalytic step in the ATPase cycle. The interaction between the 38-kDa domain of caldesmon and tropomyosin-actin is likely to play a role in the regulation of actomyosin ATPase and contraction in smooth muscle.

Actins↗
PubMed1986

Cross-linking of myosin subfragment 1 and heavy meromyosin by use of vanadate and a bis(adenosine 5'-triphosphate) analogue.

The synthesis of a divalent ATP analogue [3,3'-dithiobis[3'(2')-O-[6-(propionylamino)hexanoyl]adenosine 5'-triphosphate] (bis22ATP)] is described in which two molecules of ATP are linked via esterification of their 3'(2')-hydroxyls to the linear dicarboxylic acid 3,3'-dithiobis[N-(5-carboxypentyl)-propionamide] [[HO2C(CH2)5NHC(O)(CH2)2S-]2]. This linkage introduces 22 atoms (a maximum of approximately 2.8 nm) between the ribose oxygens of two ATP molecules. Myosin subfragment 1 (SF1) or heavy meromyosin (HMM) readily cleave bis22ATP to bis22ADP. Upon subsequent addition of excess vanadate ion, both enzymes are rapidly inactivated by formation of a stable vanadate-bis22ADP complex at the active site. By adjustment of the reaction conditions, dimers of SF1 or HMM, both cross-linked with bis22ADP-vanadate, could be prepared. Dimers of SF1 could be separated from monomers by sucrose gradient centrifugation but not by gel filtration. These observations imply that the average Stokes radius of the dimer approximates that of the monomer, a result predicted only for monomers linked approximately side by side. Conversely, dimers of HMM were separated from HMM monomers by gel filtration, reflecting an increase in their Stokes radii. This increase, however, prevented resolution of HMM dimers from monomers by sucrose gradient centrifugation. These results and the molecular dimensions of bis22ATP suggest that the 3'-(2')-hydroxyl of ATP is no more than 1.3 nm from the surface of myosin and suggest further in the simplest interpretation that the active site is most likely located near the middle of the heads of myosin. Analytical sedimentation velocity experiments were performed in order to compare the sedimentation coefficient (s0(20),w) of the SF1 dimer formed by cross-linking to values predicted from ellipsoidal models of the dimer. The observed s0(20),w of the dimer was much closer to the range predicted for a side-to-side arrangement of SF1 monomers than the range predicted for two monomers linked end to end, a result consistent with the active site location suggested above. During the course of these experiments, unmodified SF1 was used as a control, and its sedimentation behavior was reexamined. We have corroborated the finding that the s0(20),w displayed by SF1 can be affected to a limited extent by the particular experimental parameters employed during centrifugation [Morel, J. E., & Garrigos, M. (1982) Biochemistry 21, 2679-2686].(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphate↗
PubMed1978

Heavy meromyosin binds actin with negative cooperativity.

The association of fluorescently labeled heavy meromyosin (HMM) and F-actin was measured by time-resolved fluorescence depolarization. The effects of varying the protein concentrations, temperature, KCl concentration, and pH were determined. Measurements of HMM mobility supported a model of no interaction between the two heads in the absence of actin. Measurements of actin binding, when compared with results for myosin subfragment I, indicated that the two heads of HMM do not bind independently in the rigor complex. This could result from actin-transmitted negative cooperativity or from steric inhibition due to the structure of HMM. For HMM and actin in 0.15 7 kcl at 25 degrees C: Ka = 3.9 X 10(7) M-1, deltaHco' = 36 +/- 2 J M-1, deltaSco' = 0.26 +/- 0.02 kJ M-1 K-1; the slope of ln Ka vs. [KCl]1/2 = -3.88 and the pH of maximum association was 6.9.

Actins↗
PubMed1975

The interaction of heavy meromyosin and subfragment 1 with actin. Physical measurements in the presence and absence of adenosine triphosphate.

Viscosity, turbidity, and laser-light fluctuation autocorrelations of acto-heavy merymyosin (HMM) and acto-subfragment 1 (S-1) solutions were measured under conditions where the actin-activated ATPase is close to its maximal value. The results were compared to similar data obtained in the absence of ATP where the actin and myosin fragments were completely domplexed, and in the presence of ATP but at 0.1 M KLC where the actin and HMM or S-1 were almost completely dissociated. It was found that at maximal actin activation, the viscosity, turbidity, and autocorrelation data were all much closer to the values for the completely dissociated systems than to the values for the completely complexed systems. Assuming that viscosity, turbidity, and autocorrelation measurements approximate a linear measure of binding between actin and HMM or S-1, the results suggest that at maximal actin activation less than 10% of the HMM or S-1 are bound to the actin. Therefore as was suggested previously by ultracentrifuge and kinetics studies, it appears that under conditions of maximal actin activation, most of the HMM and S-1 occur in a refractory state unable to bind to actin.

Actins↗
PubMed2003

Chemical and biological regeneration of HDTMA-modified montmorillonite after sorption with phenol.

Hexadecyltrimethylammonium (HDTMA)-modified montmorillonite (HMM) has recently been recognized as a potential sorbentto remove organic contaminants from environmental systems. Potential applications of this material highly depend on the efficiency of regenerating contaminant-sorbing HMM. In this study, we investigated a chemical (NaOH solution) and a biological (yeast Pityrosporum sp.) method to regenerate phenol-sorbing HMM. Our results showed that the sorption coefficient of phenol to HMM is not a linear function of the ratio of the substitution of HDTMA in HMM. Chemical regeneration of HMMs (0-0.7 times of its cation exchange capacity (CEC)) proved the existence of a phenol residual amount of about 3 mg x g(-1) in the HMMs tested when aqueous pH is maintained above 11. In addition, the obvious deductions in the sorption capacity of the chemically regenerated HMMs were observed after four cycles of sorption-regeneration. However, the sorption capacities of intermediate substituted HMMs (0.3-0.7 CEC) can be completely restored by bioregeneration with yeast for extended cycles of reuse. The results imply that the bioregeneration method with yeast could be a promising technique for in-situ bioremediation of phenol-contaminated groundwater in the subsurface or for treatment of phenol containing wastewater.

Adsorption↗
PubMed2006

Actin filament guidance on a chip: toward high-throughput assays and lab-on-a-chip applications.

Biological molecular motors that are constrained so that function is effectively limited to predefined nanosized tracks may be used as molecular shuttles in nanotechnological applications. For these applications and in high-throughput functional assays (e.g., drug screening), it is important that the motors propel their cytoskeletal filaments unidirectionally along the tracks with a minimal number of escape events. We here analyze the requirements for achieving this for actin filaments that are propelled by myosin II motor fragments (heavy meromyosin; HMM). First, we tested the guidance of HMM-propelled actin filaments along chemically defined borders. Here, trimethylchlorosilane (TMCS)-derivatized areas with high-quality HMM function were surrounded by SiO(2) domains where HMM did not bind actin. Guidance along the TMCS-SiO(2) border was almost 100% for filament approach angles between 0 and 20 degrees but only about 10% at approach angles near 90 degrees . A model (Clemmens, J.; Hess, H.; Lipscomb, R.; Hanein, Y.; Bohringer, K. F.; Matzke, C. M.; Bachand, G. D.; Bunker, B. C.; Vogel, V. Langmuir 2003, 19, 10967-10974) accounted for essential aspects of the data and also correctly predicted a more efficient guidance of actin filaments than previously shown for kinesin-propelled microtubules. Despite the efficient guidance at low approach angles, nanosized (<700 nm wide) TMCS tracks surrounded by SiO(2) were not effective in guiding actin filaments. Neither was there complete guidance along nanosized tracks that were surrounded by topographical barriers (walls and roof partially covering the track) unless there was also chemically based selectivity between the tracks and surroundings. In the latter case, with dually defined tracks, there was close to 100% guidance. A combined experimental and theoretical analysis, using tracks of the latter type, suggested that a track width of less than about 200-300 nm is sufficient at a high HMM surface density to achieve unidirectional sliding of actin filaments. In accord with these results, we demonstrate the long-term trapping of actin filaments on a closed-loop track (width < 250 nm). The results are discussed in relation to lab-on-a-chip applications and nanotechnology-assisted assays of actomyosin function.

Actin Cytoskeleton↗
PubMed2002

A kinetic model of the co-operative binding of calcium and ADP to scallop (Argopecten irradians) heavy meromyosin.

Analysis of the kinetics of ATP and ADP binding to scallop (Argopecten irradians) heavy meromyosin (HMM) showed that the only calcium-dependent process is the rate of ADP release. At physiological ionic strength calcium accelerated ADP release about 20-fold. Notably in the absence of calcium only one ADP bound HMM, with an affinity of 0.5-1 microM. The second nucleotide site remained unoccupied at up to 50 microM ADP yet could bind ATP rapidly. The calcium dependence of ADP-release rates showed that calcium binds co-operatively to scallop HMM with an affinity of 0.78 microM and a Hill coefficient of 1.9. Detailed interpretation of the data suggests that HMM exists in equilibrium between the on and off states and that calcium and ADP modulate the equilibrium between the two states. The on state is favoured in the presence of calcium and in the absence of both calcium and nucleotide. The off state is favoured by ADP (or ADP * P(i)) in the absence of calcium. A detailed co-operative model of the interaction of ADP and calcium with HMM is presented.

Adenosine Diphosphate↗
PubMed2006

High-molecular-mass APOBEC3G complexes restrict Alu retrotransposition.

APOBEC3G (A3G) and related deoxycytidine deaminases are potent intrinsic antiretroviral factors. A3G is expressed either as an enzymatically active low-molecular-mass (LMM) form or as an enzymatically inactive high-molecular-mass (HMM) ribonucleoprotein complex. Resting CD4 T cells exclusively express LMM A3G, where it functions as a powerful postentry restriction factor for HIV-1. Activation of CD4 T cells promotes the recruitment of LMM A3G into 5- to 15-MDa HMM complexes whose function is unknown. Using tandem affinity purification techniques coupled with MS, we identified Staufen-containing RNA-transporting granules and Ro ribonucleoprotein complexes as specific components of HMM A3G complexes. Analysis of RNAs in these complexes revealed Alu and small Y RNAs, two of the most prominent nonautonomous mobile genetic elements in human cells. These retroelement RNAs are recruited into Staufen-containing RNA-transporting granules in the presence of A3G. Retrotransposition of Alu and hY RNAs depends on the reverse transcriptase machinery provided by long interspersed nucleotide elements 1 (L1). We now show that A3G greatly inhibits L1-dependent retrotransposition of marked Alu retroelements not by inhibiting L1 function but by sequestering Alu RNAs in cytoplasmic HMM A3G complexes away from the nuclear L1 enzymatic machinery. These findings identify nonautonomous Alu and hY retroelements as natural cellular targets of A3G and highlight how different forms of A3G uniquely protect cells from the threats posed by exogenous retroviruses (LMM A3G) and endogenous retroelements (HMM A3G).

APOBEC-3G Deaminase↗
PubMed2006

Nanostructures of APOBEC3G support a hierarchical assembly model of high molecular mass ribonucleoprotein particles from dimeric subunits.

Human APOBEC3G (hA3G) is a cytidine deaminase that restricts human immunodeficiency virus (HIV)-1 infection in a vif (the virion infectivity factor from HIV)-dependent manner. hA3G from HIV-permissive activated CD4+ T-cells exists as an inactive, high molecular mass (HMM) complex that can be transformed in vitro into an active, low molecular mass (LMM) variant comparable with that of HIV-non-permissive CD4+ T-cells. Here we present low resolution structures of hA3G in HMM and LMM forms determined by small angle x-ray scattering and advanced shape reconstruction methods. The results show that LMM particles have an extended shape, dissimilar to known cytidine deaminases, featuring novel tail-to-tail dimerization. Shape analysis of LMM and HMM structures revealed how symmetric association of dimers could lead to minimal HMM variants. These observations imply that the disruption of cellular HMM particles may require regulation of protein-RNA, as well as protein-protein interactions, which has implications for therapeutic development.

APOBEC-3G Deaminase↗
PubMed2003

Identification and characterization of nonmuscle myosin II-C, a new member of the myosin II family.

A previously unrecognized nonmuscle myosin II heavy chain (NMHC II), which constitutes a distinct branch of the nonmuscle/smooth muscle myosin II family, has recently been revealed in genome data bases. We characterized the biochemical properties and expression patterns of this myosin. Using nucleotide probes and affinity-purified antibodies, we found that the distribution of NMHC II-C mRNA and protein (MYH14) is widespread in human and mouse organs but is quantitatively and qualitatively distinct from NMHC II-A and II-B. In contrast to NMHC II-A and II-B, the mRNA level in human fetal tissues is substantially lower than in adult tissues. Immunofluorescence microscopy showed distinct patterns of expression for all three NMHC isoforms. NMHC II-C contains an alternatively spliced exon of 24 nucleotides in loop I at a location analogous to where a spliced exon appears in NMHC II-B and in the smooth muscle myosin heavy chain. However, unlike neuron-specific expression of the NMHC II-B insert, the NMHC II-C inserted isoform has widespread tissue distribution. Baculovirus expression of noninserted and inserted NMHC II-C heavy meromyosin (HMM II-C/HMM II-C1) resulted in significant quantities of expressed protein (mg of protein) for HMM II-C1 but not for HMM II-C. Functional characterization of HMM II-C1 by actin-activated MgATPase activity demonstrated a V(max) of 0.55 + 0.18 s(-1), which was half-maximally activated at an actin concentration of 16.5 + 7.2 microm. HMM II-C1 translocated actin filaments at a rate of 0.05 + 0.011 microm/s in the absence of tropomyosin and at 0.072 + 0.019 microm/s in the presence of tropomyosin in an in vitro motility assay.

Alternative Splicing↗
PubMed2001

Myosin V exhibits a high duty cycle and large unitary displacement.

Myosin V is a double-headed unconventional myosin that has been implicated in organelle transport. To perform this role, myosin V may have a high duty cycle. To test this hypothesis and understand the properties of this molecule at the molecular level, we used the laser trap and in vitro motility assay to characterize the mechanics of heavy meromyosin-like fragments of myosin V (M5(HMM)) expressed in the Baculovirus system. The relationship between actin filament velocity and the number of interacting M5(HMM) molecules indicates a duty cycle of > or =50%. This high duty cycle would allow actin filament translocation and thus organelle transport by a few M5(HMM) molecules. Single molecule displacement data showed predominantly single step events of 20 nm and an occasional second step to 37 nm. The 20-nm unitary step represents the myosin V working stroke and is independent of the mode of M5(HMM) attachment to the motility surface or light chain content. The large M5(HMM) working stroke is consistent with the myosin V neck acting as a mechanical lever. The second step is characterized by an increased displacement variance, suggesting a model for how the two heads of myosin V function in processive motion.

Animals↗
PubMed1968

Electron microscopic investigations of actomyosin as a function of ionic strength.

Natural actomyosin at micro = 0.6 appears in various forms, including the regular arrowhead structures originally reported by Huxley (1), when it has been stained negatively with 1% uranyl acetate. In addition to the arrowheads, thin whiskers, 700-1200 A in length and 20 A in width, attached to the arm of the arrowheads have been demonstrated. The dimensions of the whiskers and arms of the arrowheads are practically the same as those of the light meromyosin (LMM) and the heavy meromyosin (HMM) moieties of the single myosin molecule, respectively. Changes in the electron microscopically distinguishable elements during aggregation of natural actomyosin on reduction of the ionic strength have been observed. At micro = 0.4, partial aggregation of the LMM whiskers begins to result in some parallel alignment of the arrowhead-bearing filaments (acto-HMM). In the range of micro = 0.3-0.1, the LMM whiskers merge into smooth filaments which are arranged alternatingly with arrowhead-bearing filaments. Thus, lateral aggregation of composite actomyosin filaments (acto-HMM + LMM whiskers) results with the LMM moieties as links. This view is supported by the following facts: (a) acto-HMM is devoid of whiskers and does not show lateral aggregation at micro = 0.1; (b) natural actomyosin digested with trypsin at micro = 0.6, which was followed by removal of LMM aggregates at low ionic strength, is essentially the same as acto-HMM at micro = 0.1; and (c) digestion with trypsin of natural actomyosin at micro = 0.2 for varying periods of time leads to a separation of arrowhead-bearing filaments from LMM aggregates.

Microscopy, Electron↗
PubMed1980

Effect of microinjected N-ethylmaleimide-modified heavy meromyosin on cell division in amphibian eggs.

N-Ethylmaleimide-modified heavy meromyosin (NEM-HMM) microinjected into amphibian eggs inhibits cytokinesis and the cortical contractions associated with wound closure. Injection of NEM-HMM into two-cell Rana pipiens embryos produces a zone of cleavage inhibition around the point of injection. Early furrows followed by time-lapse microcinematography are seen to slow and stop as they enter the NEM-HMM-injected zone. Arrested furrows slowly regress, leaving a large region of cytoplasm uncleaved. Few nuclei are found in these regions of cleavage inhibition. Wound closure is often inhibited by NEM-HMM, especially when this inhibitor is injected just beneath the egg cortex. We observe that the surface of an unfertilized Rana egg is covered with microvilli that disappear during the course of development. The surfaces of NEM-HMM-inhibited zones remain covered with microvilli and resemble the unfertilized egg surface.

Animals↗
PubMed1982

Effects of exogenous proteins on cytoplasmic streaming in perfused Chara cells.

Cytoplasmic streaming in characean algae is thought to be generated by interaction between subcortical actin bundles and endoplasmic myosin. Most of the existing evidence supporting this hypothesis is of a structural rather than functional nature. To obtain evidence bearing on the possible function of actin and myosin in streaming, we used perfusion techniques to introduce a number of contractile and related proteins into the cytoplasm of streaming Chara cells. Exogenous actin added at concentrations as low as 0.1 mg/ml is a potent inhibitor of streaming. Deoxyribonuclease I (DNase I), an inhibitor of amoeboid movement and fast axonal transport, does not inhibit streaming in Chara. Fluorescein-DNase I stains stress cables and microfilaments in mammalian cells but does not bind to Chara actin bundles, thus suggesting that the lack of effect on streaming is due to a surprising lack of DNase I affinity for Chara actin bundles. Heavy meromyosin (HMM) does not inhibit streaming, but fluorescein-HMM (FL-HMM), having a partially disabled EDTA ATPase, does. Quantitative fluorescence micrography provides evidence that inhibition of streaming by FL-HMM may be due to a tendency for FL-HMM to remain bound to Chara actin bundles even in the presence of MgATP. Perfusion with various control proteins, including tubulin, ovalbumin, bovine serum albumin, and irrelevant antibodies, does not inhibit streaming. These results support the hypothesis that actin and myosin function to generate cytoplasmic streaming in Chara.

Actins↗
PubMed2003

Using guide trees to construct multiple-sequence evolutionary HMMs.

MOTIVATION: Score-based progressive alignment algorithms do dynamic programming on successive branches of a guide tree. The analogous probabilistic construct is an Evolutionary HMM. This is a multiple-sequence hidden Markov model (HMM) made by combining transducers (conditionally normalised Pair HMMs) on the branches of a phylogenetic tree. METHODS: We present general algorithms for constructing an Evolutionary HMM from any Pair HMM and for doing dynamic programming to any Multiple-sequence HMM. RESULTS: Our prototype implementation, Handel, is based on the Thorne-Kishino-Felsenstein evolutionary model and is benchmarked using structural reference alignments.

Algorithms↗