K_d for the Src mutants, Abl and Src WT.

<p>The RMSF values have been averaged from MD simulations.</p

Free energy of the DFG flip transition.

<p>Free energy surfaces of Abl, Src (adapted from Ref. [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004578#pcbi.1004578.ref029" target="_blank">29</a>]), and Abl drug-resistant mutants projected on the distances between DFG Asp₄₀₄ and Lys₂₉₅ (CV1) and DFG Phe₄₀₅ and Ile₂₉₃ (Leu₁₃₇ in Src) (CV2). The free energy minima corresponding to DFG-in conformations are labeled “IN”, while “OUT” correspond to DFG-out conformations. The contour lines are drawn every 1 kcal/mol.</p

RMSF of the A-loop region and IC₅₀ values of imatinib for the studied tyrosine kinases and the designed triple mutants of Src.

<p>RMSF of the A-loop region and IC₅₀ values of imatinib for the studied tyrosine kinases and the designed triple mutants of Src.</p

Root mean square fluctuation analysis of TKs and Abl resistant mutants.

<p>(a) RMSF of Abl and Src. Fluctuations of the N-lobe (left) and of the A-loop (right) for the Abl mutants (b). and the TKs (c). Shades of red and blue identify strong and weak binders, respectively. Dotted lines are used for clarity.</p

Free energy of imatinib (un-)binding to Abl and to the T315I ‘gatekeeper’ mutant.

<p>Free energy surfaces associated to the binding of imatinib to WT Abl (top panel) and the T315I Abl “gatekeeper” mutant (bottom panel). The deepest energy minima correspond to the crystallographic binding pose and are labeled A. On the way out, B and B’ correspond to an intermediate state (metastable in WT Abl) where imatinib is in between the DFG and the <i>α</i>C helix. States C and C’ correspond to the “external binding pose”. Interestingly in Abl T315I there are two exit channels and both have an higher barrier than in the WT. The contour lines are drawn every 2 kcal/mol.</p

Free energy of the A-loop opening.

<p>Free energy surfaces of Abl, Src, and drug-resistant mutants projected on the optimal path describing the conformational change of the A-loop from open to closed in Src (CV1) and Abl (CV2). The free energy minima corresponding to an extended A-loop active-like conformation are labeled “A”, “B” is used for A-loop semi-closed (inactive) conformations and “C” for fully closed A-loop conformations. The contour lines are drawn every 1 kcal/mol.</p

Entropy and Enthalpy contributions to the DFG-in DFG-out flip as obtained from the linear regression of the Free Energy as a function of temperature.

<p>Entropy and Enthalpy contributions to the DFG-in DFG-out flip as obtained from the linear regression of the Free Energy as a function of temperature.</p