Time courses of interatomic distances of six representative bonds in binding site of 6B4/GPIbα complex.

<p>The interatomic distances of six representative bonds were plotted against simulation time, where the interatomic distances were from the oxygen atoms of acidic residues and their respective partners, the nitrogen atoms of basic residues, for three salt bridges, 5^th (A), 4^th (B) and 9^th (C) bonds, or from doners to their respective acceptors for three hydrogen bonds, 16^th (D), 10^th (E) and 1^st (F) bonds. The salt bridges and hydrogen bonds were simulated with the initial conformation I (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042263#pone-0042263-g003" target="_blank">Fig. 3 A</a>) and II (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042263#pone-0042263-g003" target="_blank">Fig. 3 B</a>), respectively. The gray dashed line expresses the distance cut-off of 0.35 nm beyond which the bonds breaks, and the blue, green and red lines exhibit the variation of interatomic distances (nm) of a bond against simulation time (ns) for thrice-repeat independent free MD simulations, respectively. The thermal stabilizations of the 4^th and 10^th bonds (B and E) seemed to be higher than those of the 5^th and 16^th bonds but lower than those of the 9^th and 1^st bonds. Remarkable difference in the thrice-repeat independent simulations showed a random behavior of intermolecular interactions.</p

Comparison between values of spring constant <i>k</i> (white bars) read from slopes of <i>F</i>-<i>x/L</i> curves (<b>Fig. 1 <b><i>A</i></b></b>) and those (gray bars) estimated by fitting <i>x/L</i>-<i>t</i> curves (<b>Fig. 3</b>) with Langevin equation (Eq. 1) in the region of <i>x/L</i> from zero to 0.2 for HP(2–20), HPA1, HPA2, HPA3 and HPA5, respectively.

<p>The data are presented as mean ± SE of five different values of <i>k</i> extracted from five independent stretching events for each peptide. There were no statistically significant differences in the values of <i>k</i> derived from the two different methods, due to <i>p</i>-values ranging from 0.36 to 0.67 in student <i>t</i>-test, for each of the peptides. The statistical differences in <i>k</i> values among these peptides were similar to those in their corresponding Young's moduli (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016441#pone-0016441-g005" target="_blank">Fig. 5</a>).</p

Variation of survival rate of main-chain H-bonds versus the relative extension <i>x</i>/<i>L</i> for HP(2–20), HPA1, HPA2, HPA3 and HPA5, respectively.

<p>The survival rate of main-chain H-bonds is a mean of the survival ratios of main-chain H-bonds recorded in five unfolding events of different initial conformations in equilibrium for each of the peptides.</p

Mapping Paratope on Antithrombotic Antibody 6B4 to Epitope on Platelet Glycoprotein Ibalpha via Molecular Dynamic Simulations

<div><p>Binding of platelet receptor glycoprotein Ibα (GPIbα) to the A1 domain of von Willebrand factor (vWF) is a critical step in both physiologic hemostasis and pathologic thrombosis, for initiating platelet adhesion to subendothelium of blood vessels at sites of vascular injury. Gain-of-function mutations in GPIbα contribute to an abnormally high-affinity binding of platelets to vWF and can lead to thrombosis, an accurate complication causing heart attack and stroke. Of various antithrombotic monoclonal antibodies (mAbs) targeting human GPIbα, 6B4 is a potent one to inhibit the interaction between GPIbα and vWF-A1 under static and flow conditions. Mapping paratope to epitope with mutagenesis experiments, a traditional route in researches of these antithrombotic mAbs, is usually expensive and time-consuming. Here, we suggested a novel computational procedure, which combines with homology modeling, rigid body docking, free and steered molecular dynamics (MD) simulations, to identify key paratope residues on 6B4 and their partners on GPIbα, with hypothesis that the stable hydrogen bonds and salt bridges are the important linkers between paratope and epitope residues. Based on a best constructed model of 6B4 bound with GPIbα, the survival ratios and rupture times of all detected hydrogen bonds and salt bridges in binding site were examined via free and steered MD simulations and regarded as indices of thermal and mechanical stabilizations of the bonds, respectively. Five principal paratope residues with their partners were predicted with their high survival ratios and/or long rupture times of involved hydrogen bonds, or with their hydrogen bond stabilization indices ranked in top 5. Exciting, the present results were in good agreement with previous mutagenesis experiment data, meaning a wide application prospect of our novel computational procedure on researches of molecular of basis of ligand-receptor interactions, various antithrombotic mAbs and other antibodies as well as theoretically design of biomolecular drugs.</p> </div

Comparison of Young's modulus <i>E</i> of HP(2–20), HPA1, HPA2, HPA3 and HPA5.

<p>The data of <i>E</i> are presented as mean ± SE of five different values derived from the <i>k</i> values, the best fitting results of <i>x/L</i>-<i>t</i> curves of five independent stretching events for each peptide. Significant differences (<i>p</i>-values ranging from 0.01 to 0.03) lie in the <i>E</i> values among these peptides, except for the difference (<i>p</i> = 0.11) in the <i>E</i> values of HP(2–20) and HPA2.</p

A unified neural circuit of causal inference and multisensory integration

Causal inference and multisensory integration are two fundamental processes of perception. It is generally believed that there should be one unified neural circuit in the brain to realize these two processes in an optimal way. However, there is no solution yet due to the complicated neural implementation for posterior probability computation. In this study, we propose a unified neural network by solving the complicated posterior probability computation. A unified theoretical framework is presented from the viewpoint of expectation. In addition, a biologically realistic neural circuit is proposed with the combination of importance sampling and probabilistic population coding. Theoretical analyses and simulation results manifest that our proposed neural circuit can implement both causal inference and multisensory integration. Taken together, our framework provides a new perspective of how different perceptual tasks can be performed by the same neural circuit

Hydrogen bonds and salt bridges with higher stabilization in Top 8.

*<p>HBSI expresses the index of hydrogen bond stabilization (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042263#s2" target="_blank">Materials and Methods</a>).</p

Comparison of instantaneous (irregular curves) and fitted (smooth lines) time courses of the relative extension <i>x/L</i> in the region of <i>x/L</i> from zero to 0.5 for HP(2–20) (<i>A</i>) and its four analogues (<i>B</i>).

<p>The representative instantaneous time courses of <i>x/L</i> were recorded from their corresponding tensile events simulated by SMD with pulling velocity of 0.01 nm/ps and time step 2fs. The predicted time courses of <i>x/L</i> came from Eq.2, the solution of Langevin equation, with respective best fitting values (<i>A</i> and <i>B</i>) of spring constant <i>k</i> and relaxation <i>τ</i>. The simulated and fitted <i>x/L</i>–<i>t</i> curves are in well agreement with each other, except for small <i>t</i> values less than about 2<i>τ</i>.</p

The false discovery rate, sensitivity and specificity of three different positive criterions.

<p>The false discovery rate was evaluated by Eq. 1, and Eq. 3 was used to estimated the sensitivity and specificity, with use of data in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042263#pone.0042263.s006" target="_blank">Table S2</a> in Suppl. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042263#s2" target="_blank">Materials</a>.</p

The CDRs and identified paratope residues of 6B4 [16].

*<p>The positions of residues in 6B4-ScFv were expressed with serial numbering from N-terminal of heavy chain to C-terminal of light chain.</p>†<p>The serial numbers, 166, 167, 168, 233 and 106, are corresponding to those in Kabat numbering, such as 27D, 27E, 28, 93 and 100C, respectively. ^†The residue sequences, contributed to their respective CDRs (CDR H1, H2, H3, L1, L2 and L3), follow the serial numbering too.</p