Comparative protein structure modeling using MODELLER

“The quickest way to search for suitable templates in this regime is to use simple pairwise sequence alignment methods such as SSEARCH (Pearson, 1994), BLAST (Altschul et al., 1997), and FASTA (Pearson, 1994).”

“…number of variants of profile-profile alignment methods that differ in the scoring functions they use (Pietrokovski, 1996; Rychlewski et al., 1998; Yona and Levitt, 2002; Panchenko, 2003; Sadreyev and Grishin, 2003; von Ohsen et al., 2003; Edgar, 2004; Marti-Renom et al., 2004; Zhou and Zhou, 2005).”

“Additionally, the stereochemistry of the model (e.g., bond-lengths, bond-angles, backbone torsion angles, and nonbonded contacts) may be evaluated using programs such as PROCHECK (Laskowski et al., 1993) and WHATCHECK (Hooft et al., 1996).”

“In the second step, the spatial restraints and the CHARMM22 force field terms enforcing proper stereochemistry (MacKerell et al., 1998) are combined into an objective function.”

“MODELLER, the authors’ own program for comparative modeling, belongs to this group of methods (Sali and Blundell, 1993; Sali and Overington, 1994; Fiser et al., 2000; Fiser et al., 2002).”

“Although align2d() is based on a dynamic programming algorithm (Needleman and Wunsch, 1970), it is different from standard sequence-sequence alignment methods because it takes into account structural information from the template when constructing an alignment.”

“The command uses the local dynamic programming algorithm to identify related sequences (Smith and Waterman, 1981).”

“Three other programs that implement this method are 3D-JIGSAW (Bates et al., 2001), RosettaCM (Song et al., 2013), and SWISS-MODEL (Schwede et al., 2003).”

“The information in a multiple sequence alignment is most often encoded as either a position-specific scoring matrix (PSSM; Henikoff and Henikoff, 1994; Altschul et al., 1997) or as a Hidden Markov Model (HMM; Krogh et al., 1994; Eddy, 1998).”

“The ModBase database can be searched in many ways, e.g., by amino acid sequence, annotation keywords, the template used for modeling, accession number (such as from UniProt; Bairoch et al., 2005; Benson et al., 2013), gene name, or organism.”

“They include VERIFY3D (Luthy et al., 1992), Prosa, 2003 (Sippl, 1993; Wiederstein and Sippl, 2007), HARMONY (Topham et al., 1994), ANOLEA (Melo and Feytmans, 1998), DFIRE (Zhou and Zhou, 2002), DOPE (Shen and Sali, 2006), SOAP (Dong et al., 2013), QMEAN local (Benkert et al., 2011), and TSVMod…”

“As stated earlier, comparative modeling consists of four main steps: fold assignment, target-template alignment, model building, and model evaluation (Marti-Renom et al., 2000; Fig.”

“…type, and hydrogen-bonding properties (Shi et al., 2001; Karchin et al., 2003; McGuffin and Jones, 2003; Zhou and Zhou, 2005) or on statistical potentials for residue interactions implied by the alignment (Sippl, 1990; Bowie et al., 1991; Sippl, 1995; Skolnick and Kihara, 2001; Xu et al., 2003).”

“Although many loop-modeling methods have been described, it is still challenging to correctly and confidently model loops longer than (cid:2) 10 to 12 residues (Fiser et al., 2000; Jacobson et al., 2004; Zhu et al., 2006).”

“Some of the programs that can be used to detect suitable templates are FFAS (Jaroszewski et al., 2005), SP3 (Zhou and Zhou, 2005), SALIGN (Marti-Renom et al., 2004), HHBlits (Rem-mert et al., 2012), HHsearch (Soding, 2005), and PPSCAN, part of MODELLER (Sali and Blundell, 1993).”

“They include VERIFY3D (Luthy et al., 1992), Prosa, 2003 (Sippl, 1993; Wiederstein and Sippl, 2007), HARMONY (Topham et al., 1994), ANOLEA (Melo and Feytmans, 1998), DFIRE (Zhou and Zhou, 2002), DOPE (Shen and Sali, 2006), SOAP (Dong et al., 2013), QMEAN local (Benkert et al., 2011), and TSVMod (Eramian et al., 2008).”

“Some of the programs that can be used to detect suitable templates are FFAS (Jaroszewski et al., 2005), SP3 (Zhou and Zhou, 2005), SALIGN (Marti-Renom et al., 2004), HHBlits (Rem-mert et al., 2012), HHsearch (Soding, 2005), and PPSCAN, part of MODELLER (Sali and Blundell, 1993).”

“…(Luthy et al., 1992), Prosa, 2003 (Sippl, 1993; Wiederstein and Sippl, 2007), HARMONY (Topham et al., 1994), ANOLEA (Melo and Feytmans, 1998), DFIRE (Zhou and Zhou, 2002), DOPE (Shen and Sali, 2006), SOAP (Dong et al., 2013), QMEAN local (Benkert et al., 2011), and TSVMod (Eramian et al., 2008).”

“Additionally, the stereochemistry of the model (e.g., bond-lengths, bond-angles, backbone torsion angles, and nonbonded contacts) may be evaluated using programs such as PROCHECK (Laskowski et al., 1993) and WHATCHECK (Hooft et al., 1996).”

“They include VERIFY3D (Luthy et al., 1992), Prosa, 2003 (Sippl, 1993; Wiederstein and Sippl, 2007), HARMONY (Topham et al., 1994), ANOLEA (Melo and Feytmans, 1998), DFIRE (Zhou and Zhou, 2002), DOPE (Shen and Sali, 2006), SOAP (Dong et al., 2013), QMEAN local (Benkert et al., 2011), and TSVMod…”

“The method was tested on a large number of loops of known structure, both in native and near-native environments (Fiser et al., 2000).”

“This protocol should also include assessment using the best computational tools currently available, such as the model assessment methods covered in this text, and those cataloged at the Protein Model Portal ( http://proteinmodelportal.org ; Arnold et al., 2009; Haas et al., 2013).”

“The information in a multiple sequence alignment is most often encoded as either a position-specific scoring matrix (PSSM; Henikoff and Henikoff, 1994; Altschul et al., 1997) or as a Hidden Markov Model (HMM; Krogh et al., 1994; Eddy, 1998).”

“…by > 30% sequence identity; (ii) the “twilight zone” (Rost, 1999), corresponding to relationships with statistically significant sequence similarity, with identities in the 10% to 30% range; and (iii) the “midnight zone” (Rost, 1999), corresponding to statistically insignificant sequence similarity.”

“ModLoop ( http://salilab.org/modloop/ ; Fiser and Sali, 2003b) takes as input a protein structure and one or more residue ranges.”

“Models with such high accuracy have been shown to be useful even for refining crystallographic structures by the method of molecular replacement (Howell et al., 1992; Baker and Sali, 2001; Jones, 2001; Claude et al., 2004; Schwarzenbacher et al., 2004).”

“Commonly used threading programs are GenTHREADER (Jones, 1999; McGuffin and Jones, 2003), 3D-PSSM (Kelley et al., 2000), FUGUE (Shi et al., 2001), SP3 (Zhou and Zhou, 2005), SAM-T08 multi-track HMM (Karchin et al., 2003; Karplus et al., 2003), and MUSTER (Wu and Zhang, 2008).”

“…search approaches that scan a database of all known protein structures to find segments fitting the anchor core regions (Jones and Thirup, 1986; Chothia and Lesk, 1987); (ii) conformational search approaches that rely on optimizing a scoring function (Moult and James, 1986; Bruccoleri and…”

“…on residue substitution tables dependent on structural features such as solvent exposure, secondary structure type, and hydrogen-bonding properties (Shi et al., 2001; Karchin et al., 2003; McGuffin and Jones, 2003; Zhou and Zhou, 2005) or on statistical potentials for residue interactions implied…”

“…accurate and efficient when a database of specific loops is created to address the modeling of the same class of loops, such as β -hairpins (Sibanda et al., 1989), or loops on a specific fold, such as the hypervariable regions in the immunoglobulin fold (Chothia and Lesk, 1987; Chothia et al., 1989).”

“For example, SAM-T08 makes use of the predicted local structure for the target sequence to enhance homolog detection and alignment accuracy (Karplus et al., 2003).”

“Three other programs that implement this method are 3D-JIGSAW (Bates et al., 2001), RosettaCM (Song et al., 2013), and SWISS-MODEL (Schwede et al., 2003).”

“The pseudo energy function is a sum of many terms, including some terms from the CHARMM22 molecular mechanics force field (MacKerell et al., 1998), spatial restraints based on distributions of distances (Sippl, 1990; Melo et al., 2002), and dihedral angles in known protein structures.”

“…Vlijmen and Karplus, 1997), genetic algorithms (Ring et al., 1993), Monte Carlo and simulated annealing (Higo et al., 1992; Collura et al., 1993; Abagyan and Totrov, 1994), multiple copy simultaneous search (Zheng et al., 1993), self-consistent field optimization (Koehl and Delarue, 1995),…”

“The identi-fication of suitable templates is achieved by scanning structure databases, such as PDB (Berman et al., 2000), SCOP (Andreeva et al., 2004), DALI (Holm et al., 2006; also see Dietmann et al., 2001), and CATH (Pearl et al., 2005), with the target sequence as the query.”

“…(Luthy et al., 1992), Prosa, 2003 (Sippl, 1993; Wiederstein and Sippl, 2007), HARMONY (Topham et al., 1994), ANOLEA (Melo and Feytmans, 1998), DFIRE (Zhou and Zhou, 2002), DOPE (Shen and Sali, 2006), SOAP (Dong et al., 2013), QMEAN local (Benkert et al., 2011), and TSVMod (Eramian et al., 2008).”

“Commonly used threading programs are GenTHREADER (Jones, 1999; McGuffin and Jones, 2003), 3D-PSSM (Kelley et al., 2000), FUGUE (Shi et al., 2001), SP3 (Zhou and Zhou, 2005), SAM-T08 multi-track HMM (Karchin et al., 2003; Karplus et al., 2003), and MUSTER (Wu and Zhang, 2008).”

“ModLoop ( http://salilab.org/modloop/ ; Fiser and Sali, 2003b) takes as input a protein structure and one or more residue ranges.”

“The basis of modeling by coordinate reconstruction is the finding that most hexapeptide segments of protein structure can be clustered into only 100 structurally different classes (Jones and Thirup, 1986; Claessens et al., 1989; Unger et al., 1989; Levitt, 1992; Bystroff and Baker, 1998).”

“The first and still widely used approach in comparative modeling is to assemble a model from a small number of rigid bodies obtained from the aligned protein structures (Browne et al., 1969; Greer, 1981; Blundell et al., 1987).”

“SAXS is a common structural characterization technique that is performed with the protein sample in solution, and usually takes only a few seconds on a well-equipped synchrotron beamline (Hura et al., 2009).”

“…type, and hydrogen-bonding properties (Shi et al., 2001; Karchin et al., 2003; McGuffin and Jones, 2003; Zhou and Zhou, 2005) or on statistical potentials for residue interactions implied by the alignment (Sippl, 1990; Bowie et al., 1991; Sippl, 1995; Skolnick and Kihara, 2001; Xu et al., 2003).”

“The optimization is carried out by the use of the variable target function method (Braun and Go, 1985), employing methods of conjugate gradients and molecular dynamics with simulated annealing (Clore et al., 1986).”

“Three other programs that implement this method are 3D-JIGSAW (Bates et al., 2001), RosettaCM (Song et al., 2013), and SWISS-MODEL (Schwede et al., 2003).”

“The basis of modeling by coordinate reconstruction is the finding that most hexapeptide segments of protein structure can be clustered into only 100 structurally different classes (Jones and Thirup, 1986; Claessens et al., 1989; Unger et al., 1989; Levitt, 1992; Bystroff and Baker, 1998).”

“The profile-sequence meth-ods are more sensitive in detecting related structures in the twilight zone than the pair-wise sequence-based methods; they detect approximately twice the number of homologs under 40% sequence identity (Park et al., 1998; Lindahl and Elofsson, 2000; Sauder et al., 2000).”

“The first and still widely used approach in comparative modeling is to assemble a model from a small number of rigid bodies obtained from the aligned protein structures (Browne et al., 1969; Greer, 1981; Blundell et al., 1987).”

“Brenner et al. (1998) showed that these methods detect only (cid:2) 18% of the homologous pairs at less than 40% sequence identity, while they identify more than 90% of the relationships when sequence identity is between 30% and 40% (Brenner et al., 1998).”

“FoXS ( http://salilab.org/foxs/ ; Schneidman-Duhovny et al., 2010) calculates a Small Angle X-ray Scattering (SAXS) profile for an uploaded protein structure and compares it with an experimental profile.”

“They include VERIFY3D (Luthy et al., 1992), Prosa, 2003 (Sippl, 1993; Wiederstein and Sippl, 2007), HARMONY (Topham et al., 1994), ANOLEA (Melo and Feytmans, 1998), DFIRE (Zhou and Zhou, 2002), DOPE (Shen and Sali, 2006), SOAP (Dong et al., 2013), QMEAN local (Benkert et al., 2011), and TSVMod…”

“Improving the performance and accuracy of methods in this regime remains one of the main tasks of comparative modeling today (Moult, 2005).”

“These scores include a normalized (z-score) version of DOPE as above; the GA341 score (Melo and Sali, 2007); ModPipe’s own quality score (MPQS; Pieper et al., 2011), which is a linear combination of DOPE, GA341, and other scores; and a prediction from TSVMod (Eramian et al., 2008) of the C α root-mean-squared deviatio…”

“Multiple alignments are generally more reliable than pair-wise alignments (Barton and Sternberg, 1987; Taylor et al., 1994).”

“…is accurate and efficient when a database of specific loops is created to address the modeling of the same class of loops, such as β -hairpins (Sibanda et al., 1989), or loops on a specific fold, such as the hypervariable regions in the immunoglobulin fold (Chothia and Lesk, 1987; Chothia et…”

“…1992; Collura et al., 1993; Abagyan and Totrov, 1994), multiple copy simultaneous search (Zheng et al., 1993), self-consistent field optimization (Koehl and Delarue, 1995), robotics-inspired kinematic closure (Mandell et al., 2009), and enumeration based on graph theory (Samudrala and Moult, 1998).”

“…be obtained either by scanning all known protein structures, including those that are not related to the sequence being modeled (Claessens et al., 1989; Holm and Sander, 1991), or by a conformational search restrained by an energy function (Bruccoleri and Karplus, 1987; van Gelder et al., 1994).”

“The information in a multiple sequence alignment is most often encoded as either a position-specific scoring matrix (PSSM; Henikoff and Henikoff, 1994; Altschul et al., 1997) or as a Hidden Markov Model (HMM; Krogh et al., 1994; Eddy, 1998).”

“Current Protocols in Protein Science Supplement 86 1997b).”

“Modeling Using MODELLER 2.9.22 Supplement 86 Current Protocols in Protein Science have the same conformation (Kabsch and Sander, 1984; Mezei, 1998).”

“Commonly used threading programs are GenTHREADER (Jones, 1999; McGuffin and Jones, 2003), 3D-PSSM (Kelley et al., 2000), FUGUE (Shi et al., 2001), SP3 (Zhou and Zhou, 2005), SAM-T08 multi-track HMM (Karchin et al., 2003; Karplus et al., 2003), and MUSTER (Wu and Zhang, 2008).”

“The accuracy of loop predictions can be further improved by clustering the sampled loop conformations and partially accounting for the entropic contribution to the free energy (Xiang et al., 2002).”

“Fortunately, the active and binding sites are frequently more conserved than the rest of the fold, and are thus modeled more accurately (Sanchez and Sali, 1998).”

“…mutations and cross-overs; (2) comparative models corresponding to these alignments are built by satisfaction of spatial restraints, as implemented in the program MODELLER; and (3) the models are assessed by a composite score, partly depending on an atomic statistical potential (Melo et al., 2002).”

“…on structural features such as solvent exposure, secondary structure type, and hydrogen-bonding properties (Shi et al., 2001; Karchin et al., 2003; McGuffin and Jones, 2003; Zhou and Zhou, 2005) or on statistical potentials for residue interactions implied by the alignment (Sippl, 1990; Bowie et…”

“The basis of modeling by coordinate reconstruction is the finding that most hexapeptide segments of protein structure can be clustered into only 100 structurally different classes (Jones and Thirup, 1986; Claessens et al., 1989; Unger et al., 1989; Levitt, 1992; Bystroff and Baker, 1998).”

“The simultaneous use of several templates can minimize this kind of error (Srinivasan and Blundell, 1993; Sanchez and Sali, 1997a, 1997b).”

“…be obtained either by scanning all known protein structures, including those that are not related to the sequence being modeled (Claessens et al., 1989; Holm and Sander, 1991), or by a conformational search restrained by an energy function (Bruccoleri and Karplus, 1987; van Gelder et al., 1994).”

“The second way of improving the alignment is to iteratively modify those regions in the alignment that correspond to predicted errors in the model (Sanchez and Sali, 1997a, 1997b; John and Sali, 2003).”

“…tables dependent on structural features such as solvent exposure, secondary structure type, and hydrogen-bonding properties (Shi et al., 2001; Karchin et al., 2003; McGuffin and Jones, 2003; Zhou and Zhou, 2005) or on statistical potentials for residue interactions implied by the alignment…”

“MODELLER, the authors’ own program for comparative modeling, belongs to this group of methods (Sali and Blundell, 1993; Sali and Overington, 1994; Fiser et al., 2000; Fiser et al., 2002).”

“To ameliorate this problem, one can use an iterative method that optimizes both the alignment and the model implied by it (Sanchez and Sali, 1997a; Miwa et al., 1999).”

“The first and still widely used approach in comparative modeling is to assemble a model from a small number of rigid bodies obtained from the aligned protein structures (Browne et al., 1969; Greer, 1981; Blundell et al., 1987).”

“…a number of variants of profile-profile alignment methods that differ in the scoring functions they use (Pietrokovski, 1996; Rychlewski et al., 1998; Yona and Levitt, 2002; Panchenko, 2003; Sadreyev and Grishin, 2003; von Ohsen et al., 2003; Edgar, 2004; Marti-Renom et al., 2004; Zhou and Zhou,…”

“…1998); in annotating single nucleotide polymorphisms (Mirkovic et al., 2004; Karchin et al., 2005); in structural characterization of large complexes by docking to low-resolution cryo-electron density maps (Spahn et al., 2001; Gao et al., 2003); and in rationalizing known experimental observations.”

“…number of variants of profile-profile alignment methods that differ in the scoring functions they use (Pietrokovski, 1996; Rychlewski et al., 1998; Yona and Levitt, 2002; Panchenko, 2003; Sadreyev and Grishin, 2003; von Ohsen et al., 2003; Edgar, 2004; Marti-Renom et al., 2004; Zhou and Zhou, 2005).”

“…al., 2006; Sellers et al., 2008), molecular dynamics simulations (Bruccoleri and Karplus, 1990; van Vlijmen and Karplus, 1997), genetic algorithms (Ring et al., 1993), Monte Carlo and simulated annealing (Higo et al., 1992; Collura et al., 1993; Abagyan and Totrov, 1994), multiple copy…”

“The accuracy of the models calculated by many of these servers is evaluated by CAMEO (Haas et al., 2013) and the biannual CASP (Critical Assessment of Techniques for Proteins Structure Prediction; Moult, 2005; Moult et al., 2009) experiment.”

“…a database of all known protein structures to find segments fitting the anchor core regions (Jones and Thirup, 1986; Chothia and Lesk, 1987); (ii) conformational search approaches that rely on optimizing a scoring function (Moult and James, 1986; Bruccoleri and Karplus, 1987; Shenkin et al., 1987).”

“The identi-fication of suitable templates is achieved by scanning structure databases, such as PDB (Berman et al., 2000), SCOP (Andreeva et al., 2004), DALI (Holm et al., 2006; also see Dietmann et al., 2001), and CATH (Pearl et al., 2005), with the target sequence as the query.”

“Commonly used threading programs are GenTHREADER (Jones, 1999; McGuffin and Jones, 2003), 3D-PSSM (Kelley et al., 2000), FUGUE (Shi et al., 2001), SP3 (Zhou and Zhou, 2005), SAM-T08 multi-track HMM (Karchin et al., 2003; Karplus et al., 2003), and MUSTER (Wu and Zhang, 2008).”

“The optimization is carried out by the use of the variable target function method (Braun and Go, 1985), employing methods of conjugate gradients and molecular dynamics with simulated annealing (Clore et al., 1986).”

“The basis of modeling by coordinate reconstruction is the finding that most hexapeptide segments of protein structure can be clustered into only 100 structurally different classes (Jones and Thirup, 1986; Claessens et al., 1989; Unger et al., 1989; Levitt, 1992; Bystroff and Baker, 1998).”

“…a database of all known protein structures to find segments fitting the anchor core regions (Jones and Thirup, 1986; Chothia and Lesk, 1987); (ii) conformational search approaches that rely on optimizing a scoring function (Moult and James, 1986; Bruccoleri and Karplus, 1987; Shenkin et al., 1987).”

“…modeling substrate specificity (Xu et al., 1996); in predicting antigenic epitopes (Sali and Blundell, 1993); in simulating protein-protein docking (Vakser, 1995); in inferring function from calculated electrostatic potential around the protein (Matsumoto et al., 1995); in facilitating molecular…”

“The quickest way to search for suitable templates in this regime is to use simple pairwise sequence alignment methods such as SSEARCH (Pearson, 1994), BLAST (Altschul et al., 1997), and FASTA (Pearson, 1994).”

“…(How-ell et al., 1992); in refining models based on NMR constraints (Modi et al., 1996); in testing and improving a sequence-structure alignment (Wolf et al., 1998); in annotating single nucleotide polymorphisms (Mirkovic et al., 2004; Karchin et al., 2005); in structural characterization of…”

“…in testing and improving a sequence-structure alignment (Wolf et al., 1998); in annotating single nucleotide polymorphisms (Mirkovic et al., 2004; Karchin et al., 2005); in structural characterization of large complexes by docking to low-resolution cryo-electron density maps (Spahn et al.,…”

“There are a number of variants of profile-profile alignment methods that differ in the scoring functions they use (Pietrokovski, 1996; Rychlewski et al., 1998; Yona and Levitt, 2002; Panchenko, 2003; Sadreyev and Grishin, 2003; von Ohsen et al., 2003; Edgar, 2004; Marti-Renom et al., 2004; Zhou and…”

“…(Fine et al., 1986), dihedral angle search through a rotamer library (Zhu et al., 2006; Sellers et al., 2008), molecular dynamics simulations (Bruccoleri and Karplus, 1990; van Vlijmen and Karplus, 1997), genetic algorithms (Ring et al., 1993), Monte Carlo and simulated annealing (Higo et…”

“The search algorithms include the minimum perturbation method (Fine et al., 1986), dihedral angle search through a rotamer library (Zhu et al., 2006; Sellers et al., 2008), molecular dynamics simulations (Bruccoleri and Karplus, 1990; van Vlijmen and Karplus, 1997), genetic algorithms (Ring et al.,…”

“…a given binding site (Ring et al., 1993; Li et al., 1996; Selzer et al., 1997; Enyedy et al., 2001; Que et al., 2002); modeling substrate specificity (Xu et al., 1996); in predicting antigenic epitopes (Sali and Blundell, 1993); in simulating protein-protein docking (Vakser, 1995); in inferring…”

“…tables dependent on structural features such as solvent exposure, secondary structure type, and hydrogen-bonding properties (Shi et al., 2001; Karchin et al., 2003; McGuffin and Jones, 2003; Zhou and Zhou, 2005) or on statistical potentials for residue interactions implied by the alignment…”

“There are attempts to classify loop conformations into more general categories, thus extending the applicability of the database search approach (Ring et al., 1992; Oliva et al., 1997; Rufino et al., 1997; Fernandez-Fuentes and Fiser, 2006).”

“The profile-sequence meth-ods are more sensitive in detecting related structures in the twilight zone than the pair-wise sequence-based methods; they detect approximately twice the number of homologs under 40% sequence identity (Park et al., 1998; Lindahl and Elofsson, 2000; Sauder et al., 2000).”

“The resulting profile-sequence alignments correctly align approximately 43% to 48% of residues in the 0% to 40% sequence identity range (Sauder et al., 2000; Marti-Renom et al., 2004); this number is almost twice as large as that of the pair-wise sequence methods.”

“The identi-fication of suitable templates is achieved by scanning structure databases, such as PDB (Berman et al., 2000), SCOP (Andreeva et al., 2004), DALI (Holm et al., 2006; also see Dietmann et al., 2001), and CATH (Pearl et al., 2005), with the target sequence as the query.”

“The accuracy of the models calculated by many of these servers is evaluated by CAMEO (Haas et al., 2013) and the biannual CASP (Critical Assessment of Techniques for Proteins Structure Prediction; Moult, 2005; Moult et al., 2009) experiment.”

“The basis of modeling by coordinate reconstruction is the finding that most hexapeptide segments of protein structure can be clustered into only 100 structurally different classes (Jones and Thirup, 1986; Claessens et al., 1989; Unger et al., 1989; Levitt, 1992; Bystroff and Baker, 1998).”

“Models with such high accuracy have been shown to be useful even for refining crystallographic structures by the method of molecular replacement (Howell et al., 1992; Baker and Sali, 2001; Jones, 2001; Claude et al., 2004; Schwarzenbacher et al., 2004).”

“…angle search through a rotamer library (Zhu et al., 2006; Sellers et al., 2008), molecular dynamics simulations (Bruccoleri and Karplus, 1990; van Vlijmen and Karplus, 1997), genetic algorithms (Ring et al., 1993), Monte Carlo and simulated annealing (Higo et al., 1992; Collura et al., 1993;…”

“The AllosMod Web server ( http://salilab.org/allosmod/ ; Weinkam et al., 2012) predicts conformational differences that may occur in the native ensemble in solution, such as those representing allosteric conformational transitions.”

“…1992; Collura et al., 1993; Abagyan and Totrov, 1994), multiple copy simultaneous search (Zheng et al., 1993), self-consistent field optimization (Koehl and Delarue, 1995), robotics-inspired kinematic closure (Mandell et al., 2009), and enumeration based on graph theory (Samudrala and Moult, 1998).”

“…in designing mutants to test hypotheses about the protein’s function (Wu et al., 1999; Vernal et al., 2002); in identifying active and binding sites (Sheng et al., 1996); in searching for, designing, and improving ligand binding strength for a given binding site (Ring et al., 1993; Li et al.,…”

“D model for a protein that is related to at least one known protein structure (Marti-Renom et al., 2000; Fiser, 2004; Misura and Baker, 2005; Petrey and Honig, 2005; Misura et al., 2006).”

“…al., 1995); in facilitating molecular replacement in X-ray structure determination (How-ell et al., 1992); in refining models based on NMR constraints (Modi et al., 1996); in testing and improving a sequence-structure alignment (Wolf et al., 1998); in annotating single nucleotide polymorphisms…”

“D model for a protein that is related to at least one known protein structure (Marti-Renom et al., 2000; Fiser, 2004; Misura and Baker, 2005; Petrey and Honig, 2005; Misura et al., 2006).”

“Currently, ModBase includes a model dataset for each of 65 complete genomes, as well as datasets for all sequences in the Structure Function Linkage Database (SFLD; Pegg et al., 2006), and for the complete SwissProt/TrEMBL database as of 2005.”

“There are also methods that combine these two approaches (van Vlijmen and Karplus, 1997; Deane and Blundell, 2001).”

“The identi-fication of suitable templates is achieved by scanning structure databases, such as PDB (Berman et al., 2000), SCOP (Andreeva et al., 2004), DALI (Holm et al., 2006; also see Dietmann et al., 2001), and CATH (Pearl et al., 2005), with the target sequence as the query.”

“They include VERIFY3D (Luthy et al., 1992), Prosa, 2003 (Sippl, 1993; Wiederstein and Sippl, 2007), HARMONY (Topham et al., 1994), ANOLEA (Melo and Feytmans, 1998), DFIRE (Zhou and Zhou, 2002), DOPE (Shen and Sali, 2006), SOAP (Dong et al., 2013), QMEAN local (Benkert et al., 2011), and TSVMod (Eramian et al., 2008).”

“…energy can be added to the scoring function for optimization, or it can be used to rank the sampled loop conformations after they are generated with a scoring function that does not include the solvent terms (Fiser et al., 2000; Felts et al., 2002; de Bakker et al., 2003; DePristo et al., 2003).”

“Even some side-chain modeling methods (Chinea et al., 1995) and the class of loop-construction methods based on finding suitable fragments in the database of known structures (Jones and Thirup, 1986) can be seen as segment-matching or coordinate-reconstruction methods.”

“…energy can be added to the scoring function for optimization, or it can be used to rank the sampled loop conformations after they are generated with a scoring function that does not include the solvent terms (Fiser et al., 2000; Felts et al., 2002; de Bakker et al., 2003; DePristo et al., 2003).”

“These methods have proven to include the most sensitive and accurate fold assignment and alignment protocols to date (Edgar and Sjolander, 2004; Marti-Renom et al., 2004; Ohlson et al., 2004; Wang and Dunbrack, 2004).”

“These methods have proven to include the most sensitive and accurate fold assignment and alignment protocols to date (Edgar and Sjolander, 2004; Marti-Renom et al., 2004; Ohlson et al., 2004; Wang and Dunbrack, 2004).”

“This protocol should also include assessment using the best computational tools currently available, such as the model assessment methods covered in this text, and those cataloged at the Protein Model Portal ( http://proteinmodelportal.org ; Arnold et al., 2009; Haas et al., 2013).”

“There are attempts to classify loop conformations into more general categories, thus extending the applicability of the database search approach (Ring et al., 1992; Oliva et al., 1997; Rufino et al., 1997; Fernandez-Fuentes and Fiser, 2006).”

“For example, the location of a binding site can be predicted from clusters of charged residues (Matsumoto et al., 1995), and the size of a ligand may be predicted from the volume of the binding-site cleft (Xu et al., 1996).”

“If several models are calculated for the same target, the best model can be selected by picking the model with the lowest value of the MODELLER objective function or the DOPE (Shen and Sali, 2006) or SOAP (Dong et al., 2013) assessment scores, which are reported at the end of the log file.”

“For example, an elegant distance geometry approach constructs all-atom models from lower and upper bounds on distances and dihedral angles (Havel and Snow, 1991).”

“…database methods are limited because the number of possible conformations increases exponentially with the length of a loop, and until the late 1990s only loops up to 7 residues long could be modeled using the database of known protein structures (Fidelis et al., 1994; Lessel and Schomburg, 1994).”

“…potentials of mean force (Sippl, 1990), nuclear magnetic resonance (NMR) experiments (Sutcliffe et al., 1992), cross-linking experiments, flu-orescence spectroscopy, image reconstruction in electron microscopy, site-directed mutagenesis (Boissel et al., 1993), and intuition, among other sources.”

“…energy can be added to the scoring function for optimization, or it can be used to rank the sampled loop conformations after they are generated with a scoring function that does not include the solvent terms (Fiser et al., 2000; Felts et al., 2002; de Bakker et al., 2003; DePristo et al., 2003).”

“The simultaneous use of several templates can minimize this kind of error (Srinivasan and Blundell, 1993; Sanchez and Sali, 1997a, 1997b).”

“The search algorithms include the minimum perturbation method (Fine et al., 1986), dihedral angle search through a rotamer library (Zhu et al., 2006; Sellers et al., 2008), molecular dynamics simulations (Bruccoleri and Karplus, 1990; van Vlijmen and Karplus, 1997), genetic algorithms (Ring et al.,…”

“They include VERIFY3D (Luthy et al., 1992), Prosa, 2003 (Sippl, 1993; Wiederstein and Sippl, 2007), HARMONY (Topham et al., 1994), ANOLEA (Melo and Feytmans, 1998), DFIRE (Zhou and Zhou, 2002), DOPE (Shen and Sali, 2006), SOAP (Dong et al., 2013), QMEAN local (Benkert et al., 2011), and TSVMod…”

“Multiple alignments are generally more reliable than pair-wise alignments (Barton and Sternberg, 1987; Taylor et al., 1994).”

“…binding sites (Sheng et al., 1996); in searching for, designing, and improving ligand binding strength for a given binding site (Ring et al., 1993; Li et al., 1996; Selzer et al., 1997; Enyedy et al., 2001; Que et al., 2002); modeling substrate specificity (Xu et al., 1996); in predicting…”

“The native and mutated enzymes were subsequently expressed and their activities compared (Wu et al., 1999).”

“Fourth, the loops are generated by scanning a database of all known protein structures to identify the structurally variable regions that fit the anchor core regions and have a compatible sequence (Topham et al., 1993).”

“These scores include a normalized (z-score) version of DOPE as above; the GA341 score (Melo and Sali, 2007); ModPipe’s own quality score (MPQS; Pieper et al., 2011), which is a linear combination of DOPE, GA341, and other scores; and a prediction from TSVMod (Eramian et al., 2008) of the C α…”

“There are a number of variants of profile-profile alignment methods that differ in the scoring functions they use (Pietrokovski, 1996; Rychlewski et al., 1998; Yona and Levitt, 2002; Panchenko, 2003; Sadreyev and Grishin, 2003; von Ohsen et al., 2003; Edgar, 2004; Marti-Renom et al., 2004; Zhou and…”

“MODELLER, the authors’ own program for comparative modeling, belongs to this group of methods (Sali and Blundell, 1993; Sali and Overington, 1994; Fiser et al., 2000; Fiser et al., 2002).”

“…(Modi et al., 1996); in testing and improving a sequence-structure alignment (Wolf et al., 1998); in annotating single nucleotide polymorphisms (Mirkovic et al., 2004; Karchin et al., 2005); in structural characterization of large complexes by docking to low-resolution cryo-electron density…”

“Accuracies of the various model-building methods are relatively similar when used optimally (Marti-Renom et al., 2002).”

“These methods have proven to include the most sensitive and accurate fold assignment and alignment protocols to date (Edgar and Sjolander, 2004; Marti-Renom et al., 2004; Ohlson et al., 2004; Wang and Dunbrack, 2004).”

“…1992; Collura et al., 1993; Abagyan and Totrov, 1994), multiple copy simultaneous search (Zheng et al., 1993), self-consistent field optimization (Koehl and Delarue, 1995), robotics-inspired kinematic closure (Mandell et al., 2009), and enumeration based on graph theory (Samudrala and Moult,…”

“…et al., 1996); in searching for, designing, and improving ligand binding strength for a given binding site (Ring et al., 1993; Li et al., 1996; Selzer et al., 1997; Enyedy et al., 2001; Que et al., 2002); modeling substrate specificity (Xu et al., 1996); in predicting antigenic epitopes (Sali…”

“Modeling Using MODELLER 2.9.22 Supplement 86 Current Protocols in Protein Science have the same conformation (Kabsch and Sander, 1984; Mezei, 1998).”

“Models with such high accuracy have been shown to be useful even for refining crystallographic structures by the method of molecular replacement (Howell et al., 1992; Baker and Sali, 2001; Jones, 2001; Claude et al., 2004; Schwarzenbacher et al., 2004).”

“They include VERIFY3D (Luthy et al., 1992), Prosa, 2003 (Sippl, 1993; Wiederstein and Sippl, 2007), HARMONY (Topham et al., 1994), ANOLEA (Melo and Feytmans, 1998), DFIRE (Zhou and Zhou, 2002), DOPE (Shen and Sali, 2006), SOAP (Dong et al., 2013), QMEAN local (Benkert et al., 2011), and TSVMod…”

“…and Karplus, 1990; van Vlijmen and Karplus, 1997), genetic algorithms (Ring et al., 1993), Monte Carlo and simulated annealing (Higo et al., 1992; Collura et al., 1993; Abagyan and Totrov, 1994), multiple copy simultaneous search (Zheng et al., 1993), self-consistent field optimization (Koehl and…”

“The search algorithms include the minimum perturbation method (Fine et al., 1986), dihedral angle search through a rotamer library (Zhu et al., 2006; Sellers et al., 2008), molecular dynamics simulations (Bruccoleri and Karplus, 1990; van Vlijmen and Karplus, 1997), genetic algorithms (Ring et al.,…”

“…in searching for, designing, and improving ligand binding strength for a given binding site (Ring et al., 1993; Li et al., 1996; Selzer et al., 1997; Enyedy et al., 2001; Que et al., 2002); modeling substrate specificity (Xu et al., 1996); in predicting antigenic epitopes (Sali and Blundell, 1993);…”

“…and improving ligand binding strength for a given binding site (Ring et al., 1993; Li et al., 1996; Selzer et al., 1997; Enyedy et al., 2001; Que et al., 2002); modeling substrate specificity (Xu et al., 1996); in predicting antigenic epitopes (Sali and Blundell, 1993); in simulating…”

“…database methods are limited because the number of possible conformations increases exponentially with the length of a loop, and until the late 1990s only loops up to 7 residues long could be modeled using the database of known protein structures (Fidelis et al., 1994; Lessel and Schomburg, 1994).”

“D model for a protein that is related to at least one known protein structure (Marti-Renom et al., 2000; Fiser, 2004; Misura and Baker, 2005; Petrey and Honig, 2005; Misura et al., 2006).”

“Average lDDT scores (a) for ProMod3/MODELLER: 59.04/57.54, average MolProbity overall scores (b): 1.70/3.07, average MolProbity clash scores (c): 5.18/85.31, average MolProbity rotamer outliers (d): 1.61/3.30 and average MolProbity Ramachandran outliers (e): 1.64/1.59.”

“For SARS-CoV-2, the three dimensional (3D) RBD structure was modeled based on the RBD structure of SARS-CoV using the MODELLER program [37], where the sequence alignment was performed using the ClustalW program [38,39].”

“The options for the results analysis include: (i) customization of the output parameters; (ii) optional MODELLER-based (Webb and Sali, 2016) all-atom reconstruction (including hydrogen atoms); (iii) customizable clustering and filtering; (iv) contact map calculation and visualization (contact maps provide residue-to-r…”

“In the final alignment, the percentage of identical residues between nhTMEM16 and mTMC1 was ~13% and was used in the MODELLER package (Webb and Sali, 2016), where 2000 modeling iterations were performed.”

“We attempted to identify templates for all these targets using HHPred [32] with default settings and built homology models of the dimers using MODELLER [33] from the templates found.”

“tion steps, the dihedral angles of residues 37 to 54 and 265 to 279 (forming the ion pore) were restrained for the first 10 nanosecond of production, with a force constant of 500kcal/mol/rad.(25)”

“An example of homology model computed with MODELER software [38] using the structure of Rv2431 as a template (sequence identity 30%), is reported for PE_PGRS30 in Figure 2f.”

“This sequence was used to predict the structure of Mpro in its biologically active conformation (dimer) by using Modeller (Ho et al., 2015; Webb and Sali, 2016); the following structures were used as templates (PDB ids): 2AMD, 1WOF, 2AMQ, 2D2D, 3E91, and 3EA7 (Yang et al.”

“Structural geometry confirmation MODELLER [33] Free standalone program for academic license or commercially available through BIOVIA https://salilab.”

“We built the new resource by re-using the GPCRdb framework (15–17) which uses a Django Framework and the packages BioPython (18), NumPy (19), SciPy (20), and MODELLER (21).”

“A sequence alignment was constructed on the basis of the aligned structures and was used for multi-template modeling in MODELER (Webb and Sali, 2016).”

“Missing loops in 6M71 were replaced using MODELLER [27].”

“One hundred homology models of the activated D 2 R bound to agonist ligand (PD128907) were constructed using MODELLER 56 version 10.2 based on a cryo-EM structure of the D 3 dopamine receptor complexed with the G i protein 57 (PDB accession code: 7CMV) as a template.”

“The homology modeling was carried out using the MODELLER software ( 69 ), and after 300 iterations, the best MsbA E. coli structural model was selected according to the discrete optimized protein energy (DOPE) score.”

“1 66 .”

“Missing residues that were not solved in 3fcs (746–774 and 840–873 in chain A, and 75–78 and 477–482 in chain B) were modelled using Modeller (Webb and Sali, 2016) with 3ije as a template.”

“16) (Webb and Sali, 2016), with templates of the crystal structure of Con-Ins G1 (PDB 5JYQ (Menting et al.”

“The structure of the N-terminal domains (MP-Spacer) of ADAMTS7 was modeled with the Bioinformatics Toolkit of the Max Planck Institute for Developmental Biology, Tübingen, Germany (54, 55).”

“…of this spacer to the C-termini ( (cid:1) 52 A˚ apart) of a model of a disulfide-bonded dimer of hZP1-N1, generated using a combination of MODELLER 110 and AlphaFold; (3) connecting the C-termini of the resulting 2 x (hZP1-N1 + spacer) assembly to the N-termini of the trefoil domains of hZP1…”

“Homology models of mouse ZP3 ZP-C and pig ZP4 ZP-N were generated using MODELLER (Webb & Sali, 2016), based on sequence – structure alignments produced by HHpred (Zimmer-mann et al , 2018).”

“Missing parts that could not be modelled by homology to experimental data have been built using the software Modeller (Webb and Sali, 2016).”

“org/modeller/; last accessed: 17 May 2018) (35).”

“Based on sequence and secondary structure alignment, a homology model of Gn was obtained using the GP38 structure as a template via MODELLER in Chimera (45, 46).”

“Missing loops in the structure of SERCA were introduced using MODELLER software (Webb and Sali, 2016).”

“Modeller 9.20 (Webb & Sali, 2016) was used to model the lacking regions of the receptor and Scwrl4 (Krivov et al., 2009) to position the nondetermined side chains.”

“The missing residues in both structures were modeled using the MOD-ELLER software 63 by alignment to the WT human mGlu5 sequence extracted from the UniProt website (UniProt ID: P41594).”