CSAR Benchmark Exercise of 2010: Selection of the Protein–Ligand Complexes

ABSTRACT: A major goal in drug design is the improvement of computational methods for docking and scoring. The Community Structure Activity Resource (CSAR) aims to collect available data from industry and academia which may be used for this purpose (www.csardock.org). Also, CSAR is charged with organizing community-wide exercises based on the collected data. The first of these exercises was aimed to gauge the overall state of docking and scoring, using a large and diverse data set of protein ligand complexes. Participants were asked to calculate the affinity of the complexes as provided and then recalculate with changes which may improve their specific method. This first data set was selected from existing PDB entries which had binding data (Kd or Ki) in Binding MOAD, augmented with entries from PDBbind. The final data set contains 343 diverse protein ligand complexes and spans 14 pKd. Sixteen proteins have three or more complexes in the data set, from which a user could start an inspection of congeneric series. Inherent experimental error limits the possible correlation between scores and measured affinity; R 2 is limited to ∼0.9 when fitting to the data set without over parametrizing. R 2 is limited to ∼0.8 when scoring the data set with a method trained on outside data. The details of how the data set was initially selected, and the process by which it matured t

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Residues with strong correlation to nucleotide in NBD LD simulations.

<p>Residues with strong correlation to nucleotide in NBD LD simulations.</p

Activity of DnaK and its mutants.

a<p>ref. <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003279#pcbi.1003279-Chang1" target="_blank">[21]</a>.</p

Center-of-mass distance between subdomains II-B and I-A/B+II-A in Langevin Dynamics.

<p>Center-of-mass distance between subdomains II-B and I-A/B+II-A in Langevin Dynamics.</p

Conserved residues in subdomains II-A/II-B hinge region of DnaK NBD.

<p>Identity above 90% are highlighted.</p

Eigenvectors of NBD.

<p>(A) The first eigenvector of NBD essential dynamics (ED) involves a shearing motion of the domains I and II. <i>Left</i> – side view of the NBD, in which ED vectors of domains I and II are colored blue and red, respectively. <i>Right</i> – front view of the NBD. The shearing motion of domains I and II is manifested through the two helices at the interface of subdomains I-A and II-A, as indicated in the circle. (B) Second eigenvector of NBD ED involves a rotating motion of primarily subdomain II-B, which may change the distance between subdomains I-B and II-B. Subdomain II-B is colored red, and the other three subdomains are in blue.</p