The <i>syn/anti</i> patterns of the intermediates.

<p>The bases that have formed native hydrogen bonds in between are plotted side-by-side and in the same plane. The red squares denote the nucleotides with configurations, the blue the ; and the gradient color indicates a fluctuating configuration between and . The nucleotides indicated by arrows correspond to either fluctuating (with gradient color) or wrong <i>syn/anti</i> configurations. Here by wrong we mean that they retain a <i>syn/anti</i> configuration different from the native one. The details of the trajectories are given in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003562#pcbi.1003562.s011" target="_blank">Figure S11</a>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003562#pcbi.1003562.s012" target="_blank">S12</a>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003562#pcbi.1003562.s013" target="_blank">S13</a>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003562#pcbi.1003562.s014" target="_blank">S14</a>.</p

The hydrogen bond maps for the intermediates.

<p>(A)–(D) are for the intermediate-II, III, IV, and V, respectively. The formation probabilities shown here are averaged on all the structures collected from multiple conventional MD simulations. Their values are indicated by the color scales. The hydrogen bonds pointed by the red arrows are native ones that exist in the native structure, while those pointed by the white arrows are non-native ones.</p

The ion binding probabilities for the four intermediates.

<p>(A)–(D) are for the intermediate-II, III, IV, and V, respectively. The color code is the same as in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003562#pcbi-1003562-g001" target="_blank">Figure 1</a>, i.e., the red, green, and purple histograms correspond to the three G-tetrads, respectively. The black histograms indicate the binding probabilities on the non-native sites.</p

Schematic representation of the folding pathway proposed in this work.

<p>Schematic representation of the folding pathway proposed in this work.</p

The detailed tertiary structures of the intermediates.

<p>(A)–(D) are for the intermediate-II, III, IV, and V, respectively. The structures are taken from the largest cluster in the corresponding conventional MD trajectories. They are slightly different from that shown in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003562#pcbi-1003562-g001" target="_blank">Figure 1</a>, which are obtained from BEMD simulations. The non-native hydrogen bonds are plotted as blue dashed lines and pointed by blue arrows. The ions bound to DNA are shown as yellow spheres.</p

Atomistic Picture for the Folding Pathway of a Hybrid-1 Type Human Telomeric DNA G-quadruplex

<div><p>In this work we studied the folding process of the hybrid-1 type human telomeric DNA G-quadruplex with solvent and ions explicitly modeled. Enabled by the powerful bias-exchange metadynamics and large-scale conventional molecular dynamic simulations, the free energy landscape of this G-DNA was obtained for the first time and four folding intermediates were identified, including a triplex and a basically formed quadruplex. The simulations also provided atomistic pictures for the structures and cation binding patterns of the intermediates. The results showed that the structure formation and cation binding are cooperative and mutually supporting each other. The <i>syn/anti</i> reorientation dynamics of the intermediates was also investigated. It was found that the nucleotides usually take correct <i>syn/anti</i> configurations when they form native and stable hydrogen bonds with the others, while fluctuating between two configurations when they do not. Misfolded intermediates with wrong <i>syn/anti</i> configurations were observed in the early intermediates but not in the later ones. Based on the simulations, we also discussed the roles of the non-native interactions. Besides, the formation process of the parallel conformation in the first two G-repeats and the associated reversal loop were studied. Based on the above results, we proposed a folding pathway for the hybrid-1 type G-quadruplex with atomistic details, which is new and more complete compared with previous ones. The knowledge gained for this type of G-DNA may provide a general insight for the folding of the other G-quadruplexes.</p></div

The free energy landscape and the representative structures of the basins of attraction.

<p>The unit of the free energy is kcal/mol. Multiple representative structures are given for the first two basins, due to the their heterogeneous nature. The populations of the representative structures within their respectively basins are roughly estimated and indicated by the numbers beside them. The three G-tetrads in the structures are colored red, green, and purple, respectively. This color code will be used throughout the whole text unless otherwise indicated. The ions bound to DNA are shown as yellow spheres.</p