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1.  A Novel Approach of Dynamic Cross Correlation Analysis on Molecular Dynamics Simulations and Its Application to Ets1 Dimer–DNA Complex 
PLoS ONE  2014;9(11):e112419.
The dynamic cross correlation (DCC) analysis is a popular method for analyzing the trajectories of molecular dynamics (MD) simulations. However, it is difficult to detect correlative motions that appear transiently in only a part of the trajectory, such as atomic contacts between the side-chains of amino acids, which may rapidly flip. In order to capture these multi-modal behaviors of atoms, which often play essential roles, particularly at the interfaces of macromolecules, we have developed the “multi-modal DCC (mDCC)” analysis. The mDCC is an extension of the DCC and it takes advantage of a Bayesian-based pattern recognition technique. We performed MD simulations for molecular systems modeled from the (Ets1)2–DNA complex and analyzed their results with the mDCC method. Ets1 is an essential transcription factor for a variety of physiological processes, such as immunity and cancer development. Although many structural and biochemical studies have so far been performed, its DNA binding properties are still not well characterized. In particular, it is not straightforward to understand the molecular mechanisms how the cooperative binding of two Ets1 molecules facilitates their recognition of Stromelysin-1 gene regulatory elements. A correlation network was constructed among the essential atomic contacts, and the two major pathways by which the two Ets1 molecules communicate were identified. One is a pathway via direct protein-protein interactions and the other is that via the bound DNA intervening two recognition helices. These two pathways intersected at the particular cytosine bases (C110/C11), interacting with the H1, H2, and H3 helices. Furthermore, the mDCC analysis showed that both pathways included the transient interactions at their intermolecular interfaces of Tyr396–C11 and Ala327–Asn380 in multi-modal motions of the amino acid side chains and the nucleotide backbone. Thus, the current mDCC approach is a powerful tool to reveal these complicated behaviors and scrutinize intermolecular communications in a molecular system.
doi:10.1371/journal.pone.0112419
PMCID: PMC4224484  PMID: 25380315
2.  Community-wide Evaluation of Methods for Predicting the Effect of Mutations on Protein-Protein Interactions 
Proteins  2013;81(11):1980-1987.
Community-wide blind prediction experiments such as CAPRI and CASP provide an objective measure of the current state of predictive methodology. Here we describe a community-wide assessment of methods to predict the effects of mutations on protein-protein interactions. Twenty-two groups predicted the effects of comprehensive saturation mutagenesis for two designed influenza hemagglutinin binders and the results were compared with experimental yeast display enrichment data obtained using deep sequencing. The most successful methods explicitly considered the effects of mutation on monomer stability in addition to binding affinity, carried out explicit side chain sampling and backbone relaxation, and evaluated packing, electrostatic and solvation effects, and correctly identified around a third of the beneficial mutations. Much room for improvement remains for even the best techniques, and large-scale fitness landscapes should continue to provide an excellent test bed for continued evaluation of methodological improvement.
doi:10.1002/prot.24356
PMCID: PMC4143140  PMID: 23843247
CAPRI; hemagglutinin; binding; deep mutational scanning; yeast display
3.  Exhaustive comparison and classification of ligand-binding surfaces in proteins 
Many proteins function by interacting with other small molecules (ligands). Identification of ligand-binding sites (LBS) in proteins can therefore help to infer their molecular functions. A comprehensive comparison among local structures of LBSs was previously performed, in order to understand their relationships and to classify their structural motifs. However, similar exhaustive comparison among local surfaces of LBSs (patches) has never been performed, due to computational complexity. To enhance our understanding of LBSs, it is worth performing such comparisons among patches and classifying them based on similarities of their surface configurations and electrostatic potentials. In this study, we first developed a rapid method to compare two patches. We then clustered patches corresponding to the same PDB chemical component identifier for a ligand, and selected a representative patch from each cluster. We subsequently exhaustively as compared the representative patches and clustered them using similarity score, PatSim. Finally, the resultant PatSim scores were compared with similarities of atomic structures of the LBSs and those of the ligand-binding protein sequences and functions. Consequently, we classified the patches into ∼2000 well-characterized clusters. We found that about 63% of these clusters are used in identical protein folds, although about 25% of the clusters are conserved in distantly related proteins and even in proteins with cross-fold similarity. Furthermore, we showed that patches with higher PatSim score have potential to be involved in similar biological processes.
doi:10.1002/pro.2329
PMCID: PMC3795496  PMID: 23934772
protein-ligand interactions; ligand-binding site; exhaustive comparison; molecular surfaces; electrostatics potentials
4.  The Protein Data Bank archive as an open data resource 
The Protein Data Bank archive was established in 1971, and recently celebrated its 40th anniversary (Berman et al. in Structure 20:391, 2012). An analysis of interrelationships of the science, technology and community leads to further insights into how this resource evolved into one of the oldest and most widely used open-access data resources in biology.
doi:10.1007/s10822-014-9770-y
PMCID: PMC4196035  PMID: 25062767
Protein Data Bank; Protein structure; Biomacromolecules; Data archive
5.  Specific Non-Local Interactions Are Not Necessary for Recovering Native Protein Dynamics 
PLoS ONE  2014;9(3):e91347.
The elastic network model (ENM) is a widely used method to study native protein dynamics by normal mode analysis (NMA). In ENM we need information about all pairwise distances, and the distance between contacting atoms is restrained to the native value. Therefore ENM requires O(N2) information to realize its dynamics for a protein consisting of N amino acid residues. To see if (or to what extent) such a large amount of specific structural information is required to realize native protein dynamics, here we introduce a novel model based on only O(N) restraints. This model, named the ‘contact number diffusion’ model (CND), includes specific distance restraints for only local (along the amino acid sequence) atom pairs, and semi-specific non-local restraints imposed on each atom, rather than atom pairs. The semi-specific non-local restraints are defined in terms of the non-local contact numbers of atoms. The CND model exhibits the dynamic characteristics comparable to ENM and more correlated with the explicit-solvent molecular dynamics simulation than ENM. Moreover, unrealistic surface fluctuations often observed in ENM were suppressed in CND. On the other hand, in some ligand-bound structures CND showed larger fluctuations of buried protein atoms interacting with the ligand compared to ENM. In addition, fluctuations from CND and ENM show comparable correlations with the experimental B-factor. Although there are some indications of the importance of some specific non-local interactions, the semi-specific non-local interactions are mostly sufficient for reproducing the native protein dynamics.
doi:10.1371/journal.pone.0091347
PMCID: PMC3953337  PMID: 24625758
6.  The Future of the Protein Data Bank 
Biopolymers  2012;99(3):218-222.
The Worldwide Protein Data Bank (wwPDB) is the international collaboration that manages the deposition, processing and distribution of the PDB archive. The wwPDB’s mission is to maintain a single archive of macromolecular structural data that are freely and publicly available to the global community. Its members [RCSB PDB (USA), PDBe (Europe), PDBj (Japan), and BMRB (USA)] host data-deposition sites and mirror the PDB ftp archive. To support future developments in structural biology, the wwPDB partners are addressing organizational, scientific, and technical challenges.
doi:10.1002/bip.22132
PMCID: PMC3684242  PMID: 23023942
Protein Data Bank; structural biology; archive
7.  Community-wide assessment of protein-interface modeling suggests improvements to design methodology 
Fleishman, Sarel J | Whitehead, Timothy A | Strauch, Eva-Maria | Corn, Jacob E | Qin, Sanbo | Zhou, Huan-Xiang | Mitchell, Julie C. | Demerdash, Omar N.A | Takeda-Shitaka, Mayuko | Terashi, Genki | Moal, Iain H. | Li, Xiaofan | Bates, Paul A. | Zacharias, Martin | Park, Hahnbeom | Ko, Jun-su | Lee, Hasup | Seok, Chaok | Bourquard, Thomas | Bernauer, Julie | Poupon, Anne | Azé, Jérôme | Soner, Seren | Ovali, Şefik Kerem | Ozbek, Pemra | Ben Tal, Nir | Haliloglu, Türkan | Hwang, Howook | Vreven, Thom | Pierce, Brian G. | Weng, Zhiping | Pérez-Cano, Laura | Pons, Carles | Fernández-Recio, Juan | Jiang, Fan | Yang, Feng | Gong, Xinqi | Cao, Libin | Xu, Xianjin | Liu, Bin | Wang, Panwen | Li, Chunhua | Wang, Cunxin | Robert, Charles H. | Guharoy, Mainak | Liu, Shiyong | Huang, Yangyu | Li, Lin | Guo, Dachuan | Chen, Ying | Xiao, Yi | London, Nir | Itzhaki, Zohar | Schueler-Furman, Ora | Inbar, Yuval | Patapov, Vladimir | Cohen, Mati | Schreiber, Gideon | Tsuchiya, Yuko | Kanamori, Eiji | Standley, Daron M. | Nakamura, Haruki | Kinoshita, Kengo | Driggers, Camden M. | Hall, Robert G. | Morgan, Jessica L. | Hsu, Victor L. | Zhan, Jian | Yang, Yuedong | Zhou, Yaoqi | Kastritis, Panagiotis L. | Bonvin, Alexandre M.J.J. | Zhang, Weiyi | Camacho, Carlos J. | Kilambi, Krishna P. | Sircar, Aroop | Gray, Jeffrey J. | Ohue, Masahito | Uchikoga, Nobuyuki | Matsuzaki, Yuri | Ishida, Takashi | Akiyama, Yutaka | Khashan, Raed | Bush, Stephen | Fouches, Denis | Tropsha, Alexander | Esquivel-Rodríguez, Juan | Kihara, Daisuke | Stranges, P Benjamin | Jacak, Ron | Kuhlman, Brian | Huang, Sheng-You | Zou, Xiaoqin | Wodak, Shoshana J | Janin, Joel | Baker, David
Journal of molecular biology  2011;414(2):10.1016/j.jmb.2011.09.031.
The CAPRI and CASP prediction experiments have demonstrated the power of community wide tests of methodology in assessing the current state of the art and spurring progress in the very challenging areas of protein docking and structure prediction. We sought to bring the power of community wide experiments to bear on a very challenging protein design problem that provides a complementary but equally fundamental test of current understanding of protein-binding thermodynamics. We have generated a number of designed protein-protein interfaces with very favorable computed binding energies but which do not appear to be formed in experiments, suggesting there may be important physical chemistry missing in the energy calculations. 28 research groups took up the challenge of determining what is missing: we provided structures of 87 designed complexes and 120 naturally occurring complexes and asked participants to identify energetic contributions and/or structural features that distinguish between the two sets. The community found that electrostatics and solvation terms partially distinguish the designs from the natural complexes, largely due to the non-polar character of the designed interactions. Beyond this polarity difference, the community found that the designed binding surfaces were on average structurally less embedded in the designed monomers, suggesting that backbone conformational rigidity at the designed surface is important for realization of the designed function. These results can be used to improve computational design strategies, but there is still much to be learned; for example, one designed complex, which does form in experiments, was classified by all metrics as a non-binder.
doi:10.1016/j.jmb.2011.09.031
PMCID: PMC3839241  PMID: 22001016
8.  Mutational and Structural Analyses of Caldanaerobius polysaccharolyticus Man5B Reveal Novel Active Site Residues for Family 5 Glycoside Hydrolases 
PLoS ONE  2013;8(11):e80448.
CpMan5B is a glycoside hydrolase (GH) family 5 enzyme exhibiting both β-1,4-mannosidic and β-1,4-glucosidic cleavage activities. To provide insight into the amino acid residues that contribute to catalysis and substrate specificity, we solved the structure of CpMan5B at 1.6 Å resolution. The structure revealed several active site residues (Y12, N92 and R196) in CpMan5B that are not present in the active sites of other structurally resolved GH5 enzymes. Residue R196 in GH5 enzymes is thought to be strictly conserved as a histidine that participates in an electron relay network with the catalytic glutamates, but we show that an arginine fulfills a functionally equivalent role and is found at this position in every enzyme in subfamily GH5_36, which includes CpMan5B. Residue N92 is required for full enzymatic activity and forms a novel bridge over the active site that is absent in other family 5 structures. Our data also reveal a role of Y12 in establishing the substrate preference for CpMan5B. Using these molecular determinants as a probe allowed us to identify Man5D from Caldicellulosiruptor bescii as a mannanase with minor endo-glucanase activity.
doi:10.1371/journal.pone.0080448
PMCID: PMC3835425  PMID: 24278284
9.  Comment on Timely deposition of macromolecular structures is necessary for peer review by Joosten et al. (2013) 
A response to the article by Joosten et al. [(2013), Acta Cryst. D69, 2293–2295].
The wwPDB responds to the article by Joosten et al. [(2013), Acta Cryst. D69, 2293–2295].
doi:10.1107/S0907444913029168
PMCID: PMC3852647  PMID: 24311570
wwPDB; deposition; macromolecular data
10.  Comment on On the propagation of errors by Jaskolski (2013) 
A response to the article by Jaskolski [(2013), Acta Cryst. D69, 1865–1866].
The wwPDB responds to the article by Jaskolski [(2013), Acta Cryst. D69, 1865–1866].
doi:10.1107/S090744491302917X
PMCID: PMC3852648  PMID: 24311571
wwPDB; errors; 
11.  Molecular Dynamics Simulations of Double-Stranded DNA in an Explicit Solvent Model with the Zero-Dipole Summation Method 
PLoS ONE  2013;8(10):e76606.
Molecular dynamics (MD) simulations of a double-stranded DNA with explicit water and small ions were performed with the zero-dipole summation (ZD) method, which was recently developed as one of the non-Ewald methods. Double-stranded DNA is highly charged and polar, with phosphate groups in its backbone and their counterions, and thus precise treatment for the long-range electrostatic interactions is always required to maintain the stable and native double-stranded form. A simple truncation method deforms it profoundly. On the contrary, the ZD method, which considers the neutralities of charges and dipoles in a truncated subset, well reproduced the electrostatic energies of the DNA system calculated by the Ewald method. The MD simulations using the ZD method provided a stable DNA system, with similar structures and dynamic properties to those produced by the conventional Particle mesh Ewald method.
doi:10.1371/journal.pone.0076606
PMCID: PMC3790736  PMID: 24124577
12.  Exhaustive comparison and classification of ligand-binding surfaces in proteins 
Many proteins function by interacting with other small molecules (ligands). Identification of ligand-binding sites (LBS) in proteins can therefore help to infer their molecular functions. A comprehensive comparison among local structures of LBSs was previously performed, in order to understand their relationships and to classify their structural motifs. However, similar exhaustive comparison among local surfaces of LBSs (patches) has never been performed, due to computational complexity. To enhance our understanding of LBSs, it is worth performing such comparisons among patches and classifying them based on similarities of their surface configurations and electrostatic potentials. In this study, we first developed a rapid method to compare two patches. We then clustered patches corresponding to the same PDB chemical component identifier for a ligand, and selected a representative patch from each cluster. We subsequently exhaustively as compared the representative patches and clustered them using similarity score, PatSim. Finally, the resultant PatSim scores were compared with similarities of atomic structures of the LBSs and those of the ligand-binding protein sequences and functions. Consequently, we classified the patches into ∼2000 well-characterized clusters. We found that about 63% of these clusters are used in identical protein folds, although about 25% of the clusters are conserved in distantly related proteins and even in proteins with cross-fold similarity. Furthermore, we showed that patches with higher PatSim score have potential to be involved in similar biological processes.
doi:10.1002/pro.2329
PMCID: PMC3795496  PMID: 23934772
protein-ligand interactions; ligand-binding site; exhaustive comparison; molecular surfaces; electrostatics potentials
13.  Improved Estimation of Protein-Ligand Binding Free Energy by Using the Ligand-Entropy and Mobility of Water Molecules 
Pharmaceuticals  2013;6(5):604-622.
We previously developed the direct interaction approximation (DIA) method to estimate the protein-ligand binding free energy (ΔG). The DIA method estimates the ΔG value based on the direct van der Waals and electrostatic interaction energies between the protein and the ligand. In the current study, the effect of the entropy of the ligand was introduced with protein dynamic properties by molecular dynamics simulations, and the interaction between each residue of the protein and the ligand was also weighted considering the hydration of each residue. The molecular dynamics simulation of the apo target protein gave the hydration effect of each residue, under the assumption that the residues, which strongly bind the water molecules, are important in the protein-ligand binding. These two effects improved the reliability of the DIA method. In fact, the parameters used in the DIA became independent of the target protein. The averaged error of ΔG estimation was 1.3 kcal/mol and the correlation coefficient between the experimental ΔG value and the calculated ΔG value was 0.75.
doi:10.3390/ph6050604
PMCID: PMC3817721  PMID: 24276169
protein-ligand docking; molecular dynamics simulation; protein-ligand binding free energy
14.  Integration of Ligand-Based Drug Screening with Structure-Based Drug Screening by Combining Maximum Volume Overlapping Score with Ligand Doscking  
Pharmaceuticals  2012;5(12):1332-1345.
Ligand-based and structure-based drug screening methods were integrated for in silico drug development by combining the maximum-volume overlap (MVO) method with a protein-compound docking program. The MVO method is used to select reliable docking poses by calculating volume overlaps between the docking pose in question and the known ligand docking pose, if at least a single protein-ligand complex structure is known. In the present study, the compounds in a database were docked onto a target protein that had a known protein-ligand complex structure. The new score is the summation of the docking score and the MVO score, which is the measure of the volume overlap between the docking poses of the compound in question and the known ligand. The compounds were sorted according to the new score. The in silico screening results were improved by comparing the MVO score to the original docking score only. The present method was also applied to some target proteins with known ligands, and the results demonstrated that it worked well.
doi:10.3390/ph5121332
PMCID: PMC3816669  PMID: 24281339
virtual drug screening; structure-based drug screening; protein-compound docking.
15.  The Protein Data Bank at 40: Reflecting on the Past to Prepare for the Future 
A symposium celebrating the 40th anniversary of the Protein Data Bank archive (PDB), organized by the Worldwide Protein Data Bank, was held at Cold Spring Harbor Laboratory (CSHL) October 28–30, 2011. PDB40’s distinguished speakers highlighted four decades of innovation in structural biology, from the early era of structural determination to future directions for the field.
doi:10.1016/j.str.2012.01.010
PMCID: PMC3501388  PMID: 22404998
16.  Statistical Estimation of the Protein-Ligand Binding Free Energy Based On Direct Protein-Ligand Interaction Obtained by Molecular Dynamics Simulation 
Pharmaceuticals  2012;5(10):1064-1079.
We have developed a method for estimating protein-ligand binding free energy (ΔG) based on the direct protein-ligand interaction obtained by a molecular dynamics simulation. Using this method, we estimated the ΔG value statistically by the average values of the van der Waals and electrostatic interactions between each amino acid of the target protein and the ligand molecule. In addition, we introduced fluctuations in the accessible surface area (ASA) and dihedral angles of the protein-ligand complex system as the entropy terms of the ΔG estimation. The present method included the fluctuation term of structural change of the protein and the effective dielectric constant. We applied this method to 34 protein-ligand complex structures. As a result, the correlation coefficient between the experimental and calculated ΔG values was 0.81, and the average error of ΔG was 1.2 kcal/mol with the use of the fixed parameters. These results were obtained from a 2 nsec molecular dynamics simulation.
doi:10.3390/ph5101064
PMCID: PMC3816655  PMID: 24281257
protein-ligand docking; molecular dynamics simulation; protein-ligand binding free energy
17.  Non-Ewald methods: theory and applications to molecular systems 
Biophysical Reviews  2012;4(3):161-170.
Several non-Ewald methods for calculating electrostatic interactions have recently been developed, such as the Wolf method, the reaction field method, the pre-averaging method, and the zero-dipole summation method, for molecular dynamics simulations of various physical systems, including biomolecular systems. We review the theories of these approaches and their potential applications to molecular simulations, and discuss their relationships.
doi:10.1007/s12551-012-0089-4
PMCID: PMC3428531  PMID: 23293678
Molecular dynamics; Electrostatic interaction; Reaction field method; Pre-averaging method; Wolf method; Zero-dipole summation method
18.  Computer-aided antibody design 
Recent clinical trials using antibodies with low toxicity and high efficiency have raised expectations for the development of next-generation protein therapeutics. However, the process of obtaining therapeutic antibodies remains time consuming and empirical. This review summarizes recent progresses in the field of computer-aided antibody development mainly focusing on antibody modeling, which is divided essentially into two parts: (i) modeling the antigen-binding site, also called the complementarity determining regions (CDRs), and (ii) predicting the relative orientations of the variable heavy (VH) and light (VL) chains. Among the six CDR loops, the greatest challenge is predicting the conformation of CDR-H3, which is the most important in antigen recognition. Further computational methods could be used in drug development based on crystal structures or homology models, including antibody–antigen dockings and energy calculations with approximate potential functions. These methods should guide experimental studies to improve the affinities and physicochemical properties of antibodies. Finally, several successful examples of in silico structure-based antibody designs are reviewed. We also briefly review structure-based antigen or immunogen design, with application to rational vaccine development.
doi:10.1093/protein/gzs024
PMCID: PMC3449398  PMID: 22661385
antibody design; antibody engineering; protein therapeutics; vaccine design
19.  Conformational Ensembles of an Intrinsically Disordered Protein pKID with and without a KIX Domain in Explicit Solvent Investigated by All-Atom Multicanonical Molecular Dynamics 
Biomolecules  2012;2(1):104-121.
The phosphorylated kinase-inducible activation domain (pKID) adopts a helix–loop–helix structure upon binding to its partner KIX, although it is unstructured in the unbound state. The N-terminal and C-terminal regions of pKID, which adopt helices in the complex, are called, respectively, αA and αB. We performed all-atom multicanonical molecular dynamics simulations of pKID with and without KIX in explicit solvents to generate conformational ensembles. Although the unbound pKID was disordered overall, αA and αB exhibited a nascent helix propensity; the propensity of αA was stronger than that of αB, which agrees with experimental results. In the bound state, the free-energy landscape of αB involved two low free-energy fractions: native-like and non-native fractions. This result suggests that αB folds according to the induced-fit mechanism. The αB-helix direction was well aligned as in the NMR complex structure, although the αA helix exhibited high flexibility. These results also agree quantitatively with experimental observations. We have detected that the αB helix can bind to another site of KIX, to which another protein MLL also binds with the adopting helix. Consequently, MLL can facilitate pKID binding to the pKID-binding site by blocking the MLL-binding site. This also supports experimentally obtained results.
doi:10.3390/biom2010104
PMCID: PMC4030872  PMID: 24970129
IDP; phosphorylated kinase inducible domain; kinase-induced domain interacting domain; coupled folding and binding; free energy landscape; mixed lineage leukemia (MLL)
20.  Composite Structural Motifs of Binding Sites for Delineating Biological Functions of Proteins 
PLoS ONE  2012;7(2):e31437.
Most biological processes are described as a series of interactions between proteins and other molecules, and interactions are in turn described in terms of atomic structures. To annotate protein functions as sets of interaction states at atomic resolution, and thereby to better understand the relation between protein interactions and biological functions, we conducted exhaustive all-against-all atomic structure comparisons of all known binding sites for ligands including small molecules, proteins and nucleic acids, and identified recurring elementary motifs. By integrating the elementary motifs associated with each subunit, we defined composite motifs that represent context-dependent combinations of elementary motifs. It is demonstrated that function similarity can be better inferred from composite motif similarity compared to the similarity of protein sequences or of individual binding sites. By integrating the composite motifs associated with each protein function, we define meta-composite motifs each of which is regarded as a time-independent diagrammatic representation of a biological process. It is shown that meta-composite motifs provide richer annotations of biological processes than sequence clusters. The present results serve as a basis for bridging atomic structures to higher-order biological phenomena by classification and integration of binding site structures.
doi:10.1371/journal.pone.0031437
PMCID: PMC3275580  PMID: 22347478
21.  Enhanced and effective conformational sampling of protein molecular systems for their free energy landscapes 
Biophysical Reviews  2012;4(1):27-44.
Protein folding and protein–ligand docking have long persisted as important subjects in biophysics. Using multicanonical molecular dynamics (McMD) simulations with realistic expressions, i.e., all-atom protein models and an explicit solvent, free-energy landscapes have been computed for several systems, such as the folding of peptides/proteins composed of a few amino acids up to nearly 60 amino-acid residues, protein–ligand interactions, and coupled folding and binding of intrinsically disordered proteins. Recent progress in conformational sampling and its applications to biophysical systems are reviewed in this report, including descriptions of several outstanding studies. In addition, an algorithm and detailed procedures used for multicanonical sampling are presented along with the methodology of adaptive umbrella sampling. Both methods control the simulation so that low-probability regions along a reaction coordinate are sampled frequently. The reaction coordinate is the potential energy for multicanonical sampling and is a structural identifier for adaptive umbrella sampling. One might imagine that this probability control invariably enhances conformational transitions among distinct stable states, but this study examines the enhanced conformational sampling of a simple system and shows that reasonably well-controlled sampling slows the transitions. This slowing is induced by a rapid change of entropy along the reaction coordinate. We then provide a recipe to speed up the sampling by loosening the rapid change of entropy. Finally, we report all-atom McMD simulation results of various biophysical systems in an explicit solvent.
doi:10.1007/s12551-011-0063-6
PMCID: PMC3271212  PMID: 22347892
Molecular dynamics; Enhanced sampling; Generalized ensemble; Multicanonical; Canonical ensemble; Free-energy landscape
22.  Protein Data Bank Japan (PDBj): maintaining a structural data archive and resource description framework format 
Nucleic Acids Research  2011;40(Database issue):D453-D460.
The Protein Data Bank Japan (PDBj, http://pdbj.org) is a member of the worldwide Protein Data Bank (wwPDB) and accepts and processes the deposited data of experimentally determined macromolecular structures. While maintaining the archive in collaboration with other wwPDB partners, PDBj also provides a wide range of services and tools for analyzing structures and functions of proteins, which are summarized in this article. To enhance the interoperability of the PDB data, we have recently developed PDB/RDF, PDB data in the Resource Description Framework (RDF) format, along with its ontology in the Web Ontology Language (OWL) based on the PDB mmCIF Exchange Dictionary. Being in the standard format for the Semantic Web, the PDB/RDF data provide a means to integrate the PDB with other biological information resources.
doi:10.1093/nar/gkr811
PMCID: PMC3245181  PMID: 21976737
23.  HitPredict: a database of quality assessed protein–protein interactions in nine species 
Nucleic Acids Research  2010;39(Database issue):D744-D749.
Despite the availability of a large number of protein–protein interactions (PPIs) in several species, researchers are often limited to using very small subsets in a few organisms due to the high prevalence of spurious interactions. In spite of the importance of quality assessment of experimentally determined PPIs, a surprisingly small number of databases provide interactions with scores and confidence levels. We introduce HitPredict (http://hintdb.hgc.jp/htp/), a database with quality assessed PPIs in nine species. HitPredict assigns a confidence level to interactions based on a reliability score that is computed using evidence from sequence, structure and functional annotations of the interacting proteins. HitPredict was first released in 2005 and is updated annually. The current release contains 36 930 proteins with 176 983 non-redundant, physical interactions, of which 116 198 (66%) are predicted to be of high confidence.
doi:10.1093/nar/gkq897
PMCID: PMC3013773  PMID: 20947562
24.  PDBj Mine: design and implementation of relational database interface for Protein Data Bank Japan 
This article is a tutorial for PDBj Mine, a new database and its interface for Protein Data Bank Japan (PDBj). In PDBj Mine, data are loaded from files in the PDBMLplus format (an extension of PDBML, PDB's canonical XML format, enriched with annotations), which are then served for the user of PDBj via the worldwide web (WWW). We describe the basic design of the relational database (RDB) and web interfaces of PDBj Mine. The contents of PDBMLplus files are first broken into XPath entities, and these paths and data are indexed in the way that reflects the hierarchical structure of the XML files. The data for each XPath type are saved into the corresponding relational table that is named as the XPath itself. The generation of table definitions from the PDBMLplus XML schema is fully automated. For efficient search, frequently queried terms are compiled into a brief summary table. Casual users can perform simple keyword search, and 'Advanced Search' which can specify various conditions on the entries. More experienced users can query the database using SQL statements which can be constructed in a uniform manner. Thus, PDBj Mine achieves a combination of the flexibility of XML documents and the robustness of the RDB.
Database URL: http://www.pdbj.org/
doi:10.1093/database/baq021
PMCID: PMC2997606  PMID: 20798081
25.  PiRaNhA: a server for the computational prediction of RNA-binding residues in protein sequences 
Nucleic Acids Research  2010;38(Web Server issue):W412-W416.
The PiRaNhA web server is a publicly available online resource that automatically predicts the location of RNA-binding residues (RBRs) in protein sequences. The goal of functional annotation of sequences in the field of RNA binding is to provide predictions of high accuracy that require only small numbers of targeted mutations for verification. The PiRaNhA server uses a support vector machine (SVM), with position-specific scoring matrices, residue interface propensity, predicted residue accessibility and residue hydrophobicity as features. The server allows the submission of up to 10 protein sequences, and the predictions for each sequence are provided on a web page and via email. The prediction results are provided in sequence format with predicted RBRs highlighted, in text format with the SVM threshold score indicated and as a graph which enables users to quickly identify those residues above any specific SVM threshold. The graph effectively enables the increase or decrease of the false positive rate. When tested on a non-redundant data set of 42 protein sequences not used in training, the PiRaNhA server achieved an accuracy of 85%, specificity of 90% and a Matthews correlation coefficient of 0.41 and outperformed other publicly available servers. The PiRaNhA prediction server is freely available at http://www.bioinformatics.sussex.ac.uk/PIRANHA.
doi:10.1093/nar/gkq474
PMCID: PMC2896099  PMID: 20507911

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