27 research outputs found
Intermolecular Interaction Free Energies of V3 loop Residues in Complex with CCR5/CXCR4;
<p>Average intermolecular interaction free energies (y-axis) of V3 loop residues (x-axis). The intermolecular interaction free energies for every V3 loop residue are summed up for all interacting residues of CCR5 (first bar per residue) and CXCR4 (second bar per residue). The polar contribution is denoted in red and green color, for CCR5 and CXCR4, respectively, and the non-polar contribution is denoted in blue and black color, for CCR5 and CXCR4, respectively. The total interaction free energy of each V3 loop residue corresponds to the sum of polar and non-polar contributions.</p
Important intermolecular polar and non-polar interaction free energies, hydrogen bonds, salt bridges, between V3 loop and CCR5 residue pairs within the MD simulation of the complex with the lowest average binding free energy (see <i>Methods</i>).
<p>Important intermolecular polar and non-polar interaction free energies, hydrogen bonds, salt bridges, between V3 loop and CCR5 residue pairs within the MD simulation of the complex with the lowest average binding free energy (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0095767#s2" target="_blank"><i>Methods</i></a>).</p
Elucidating a Key Component of Cancer Metastasis: CXCL12 (SDF-1α) Binding to CXCR4
The chemotactic signaling induced
by the binding of chemokine CXCL12
(SDF-1α) to chemokine receptor CXCR4 is of significant biological
importance and is a potential therapeutic axis against HIV-1. However,
as CXCR4 is overexpressed in certain cancer cells, the CXCL12:CXCR4
signaling is involved in tumor metastasis, progression, angiogenesis,
and survival. Motivated by the pivotal role of the CXCL12:CXCR4 axis
in cancer, we employed a comprehensive set of computational tools,
predominantly based on free energy calculations and molecular dynamics
simulations, to obtain insights into the molecular recognition of
CXCR4 by CXCL12. We report, what is to our knowledge, the first computationally
derived CXCL12:CXCR4 complex structure which is in remarkable agreement
with experimental findings and sheds light into the functional role
of CXCL12 and CXCR4 residues which are associated with binding and
signaling. Our results reveal that the CXCL12 N-terminal domain is
firmly bound within the CXCR4 transmembrane domain, and the central
24–50 residue domain of CXCL12 interacts with the upper N-terminal
domain of CXCR4. The stability of the CXCL12:CXCR4 complex structure
is attributed to an abundance of nonpolar and polar intermolecular
interactions, including salt bridges formed between positively charged
CXCL12 residues and negatively charged CXCR4 residues. The success
of the computational protocol can mainly be attributed to the nearly
exhaustive docking conformational search, as well as the heterogeneous
dielectric implicit water-membrane-water model used to simulate and
select the optimum conformations. We also recently utilized this protocol
to elucidate the binding of an HIV-1 gp120 V3 loop in complex with
CXCR4, and a comparison between the molecular recognition of CXCR4
by CXCL12 and the HIV-1 gp120 V3 loop shows that both CXCL12 and the
HIV-1 gp120 V3 loop share the same CXCR4 binding pocket, as they mostly
interact with the same CXCR4 residues
Molecular Recognition of CCR5 by an HIV-1 gp120 V3 Loop
<div><p>The binding of protein HIV-1 gp120 to coreceptors CCR5 or CXCR4 is a key step of the HIV-1 entry to the host cell, and is predominantly mediated through the V3 loop fragment of HIV-1 gp120. In the present work, we delineate the molecular recognition of chemokine receptor CCR5 by a dual tropic HIV-1 gp120 V3 loop, using a comprehensive set of computational tools predominantly based on molecular dynamics simulations and free energy calculations. We report, what is to our knowledge, the first complete HIV-1 gp120 V3 loop : CCR5 complex structure, which includes the whole V3 loop and the N-terminus of CCR5, and exhibits exceptional agreement with previous experimental findings. The computationally derived structure sheds light into the functional role of HIV-1 gp120 V3 loop and CCR5 residues associated with the HIV-1 coreceptor activity, and provides insights into the HIV-1 coreceptor selectivity and the blocking mechanism of HIV-1 gp120 by maraviroc. By comparing the binding of the specific dual tropic HIV-1 gp120 V3 loop with CCR5 and CXCR4, we observe that the HIV-1 gp120 V3 loop residues 13–21, which include the tip, share nearly identical structural and energetic properties in complex with both coreceptors. This result paves the way for the design of dual CCR5/CXCR4 targeted peptides as novel potential anti-AIDS therapeutics.</p></div
Important Intermolecular Polar Interactions;
<p>Molecular graphics image of important polar interactions corresponding to the complex with the lowest average binding free energy. The figure shows the salt bridges and specific important hydrogen bonds. The V3 loop is shown in tube and in red color, and the residue moiety 16–20 is shown in fat tube representation. The CCR5 is shown in light gray transparent tube representation. The salt bridge and hydrogen bonds are denoted in dashed lines and the participating V3 loop and CCR5 residue moieties are shown in licorice; V3 loop and CCR5 residues are annotated in red and black, color respectively. Hydrogen atoms are omitted for clarity, and the V3 loop disulfide bridge is shown in fat transparent licorice representation.</p
HIV-1 gp120 V3 loop : CCR5 Complex Structure;
<p>Molecular graphics image of the entire simulation system corresponding to the complex with the lowest average binding free energy. The V3 loop is shown in tube and transparent surface representation in red color, and the residue moiety 16–20 is shown in fat tube representation. The CCR5 is shown in cartoon representation, and the coloring used for different protein domains is as follows: (i) N-terminal domain is colored in blue, (ii) Transmembrane helix 1 (TH1) is colored in green; (iii) Intracellular loop 1 (ICL1) is colored in light gray; (iv) TH2 is colored in purple, (v) Extracellular loop 1 (ECL1) is colored in light gray; (vi) TH3 is colored in yellow; (vii) ICL2 is colored in light gray; (viii) TH4 is colored in gray; (ix) ECL2 is colored in ochre; (x) TH5 is colored in pink; (xi) ICL3 is colored in light gray; (xii) TH6 is colored in cyan; (xiii) ECL3 is colored in lime; (xiv) TH7 is colored in orange; (xv) C-terminal domain is colored in light gray. The N-terminal Cα atom of CCR5 is shown in a small van der Waals sphere and the V3 loop disulfide bridge is shown in fat transparent licorice representation. The definition of CCR5 and V3 loop domains is presented in <i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0095767#pone.0095767.s004" target="_blank">Information S4</a></i>.</p
The trajectories explored in each system are projected on the free energy landscapes (FEL) using as reaction coordinates the projection of each trajectory along the first (PC1) and second PC2 principal components for 2B4C.
<p>(A) and 2QAD (B). The black circles show the free energy minima basins in the landscape, corresponding to the most representative structures throughout the trajectories; the structures are presented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049925#pone-0049925-g003" target="_blank">Figure 3</a> (global minimum) and Figure S7 (second and third local minima). The first (global), second, and third free energy minima are marked with A, B, C. The color code corresponding to the free energy value (z axis in kcal/mol) is shown at the right of each panel.</p
Principal Component 1 Dynamic Cross-Correlation Maps for 2B4C (A) and 2QAD (B), using C<sub>α</sub> atoms.
<p>The color code for correlation or anti-correlation is shown at the right of each figure, with black being correlated, and yellow being anti-correlated. Axes denote the residue number in sequence. The bottom panels depict “extreme” structures observed during the principal components (shown in ribbon representation in blue and red) and the movements between structures (cyan). The V3 loop structures are oriented according to the residue numbering of the DCC maps, with the tip on the left and base on the right.</p
Uncovering the Binding and Specificity of β‑Wrapins for Amyloid‑β and α‑Synuclein
Amyloidogenic proteins
amyloid-β peptide (Aβ) and α-synuclein
(α-syn) self-assemble into fibrillar amyloid deposits, senile
plaques and Lewy bodies, pathological features of Alzheimer’s
and Parkinson’s diseases, respectively. Interestingly, a portion
of Alzheimer’s disease cases also exhibit aggregation of α-syn
into Lewy bodies, and growing evidence also suggests that Aβ
and α-syn oligomers are toxic. Therefore, the simultaneous inhibition
through sequestration of the two amyloidogenic proteins may constitute
a promising therapeutic strategy. Recently discovered β-wrapin
proteins pave the way toward this direction as they can inhibit the
aggregation and toxicity of both Aβ and α-syn. Here, we
used computational methods, primarily molecular dynamics simulations
and free energy calculations, to shed light into the key interaction-based
commonalities leading to the dual binding properties of β-wrapins
for both amyloidogenic proteins, to identify which interactions potentially
act as switches diminishing β-wrapins’ binding activity
for Aβ/α-syn, and to examine the binding properties of
the current most potent β-wrapin for Aβ. Our analysis
provides insights into the distinct role of the key determinants leading
to β-wrapin binding to Aβ and α-syn, and suggests
that the Aβ <sub>18</sub>VFFAED<sub>23</sub> and α-syn <sub>38</sub>LYVGSK<sub>43</sub> are key domains determining the binding
specificity of a β-wrapin. Our findings can potentially lead
to the discovery of novel therapeutics for Alzheimer’s and
Parkinson’s diseases
Electrostatic clustering of snapshots from the minima of the V3 loop trajectories.
<p>Electrostatic potentials were calculated using ionic strength corresponding to 0 mM (A) and 150 mM (B). The graph was generated using multidimensional scaling. The axes denote coordinates that reflect the dissimilarities between snapshots. The snapshots are defined by the diameter of the circle, with smaller circles corresponding to snapshots from the beginning of the trajectory, and gradually increasing the diameter towards snapshots from the end of the trajectory. The brown, pink, and purple circles correspond to the first, second, and third minima of 2B4C (basins A, B, C in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049925#pone-0049925-g007" target="_blank">Figure 7A</a>, respectively). The red, teal, and green circles correspond to the first, second, and third minima of 2QAD (basins A, B, C in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049925#pone-0049925-g007" target="_blank">Figure 7B</a>, respectively).</p