Binding Pose Flip Explained via Enthalpic and Entropic Contributions

Abstract

The anomalous binding modes of five highly similar fragments of TIE2 inhibitors, showing three distinct binding poses, are investigated. We report a quantitative rationalization for the changes in binding pose based on molecular dynamics simulations. We investigated five fragments in complex with the transforming growth factor β receptor type 1 kinase domain. Analyses of these simulations using Grid Inhomogeneous Solvation Theory (GIST), pKA calculations, and a tool to investigate enthalpic differences upon binding unraveled the various thermodynamic contributions to the different binding modes. While one binding mode flip can be rationalized by steric repulsion, the second binding pose flip revealed a different protonation state for one of the ligands, leading to different enthalpic and entropic contributions to the binding free energy. One binding pose is stabilized by the displacement of entropically unfavored water molecules (binding pose determined by solvation entropy), ligands in the other binding pose are stabilized by strong enthalpic interactions, overcompensating the unfavorable water entropy in this pose (binding pose determined by enthalpic interactions). This analysis elucidates unprecedented details determining the flipping of the binding modes, which can elegantly explain the experimental findings for this system.

Thermodynamic Insight into the Effects of Water Displacement and Rearrangement upon Ligand Modifications using Molecular Dynamics Simulations

“…The averaged difference in interaction energy between BACE-1 and Cumming-4j (PA) and Cumming-4b (PB), respectively,a mountst oÀ7.22 kcal mol À1 .T his is accompanied by a higher entropic cost for binding for Cumming-4b (ÀTDDS bind = 1.88 kcal mol À1 ). In total, this resultsi na ne stimated change in binding free energy [see Equation (20), Experimental Section] as shown in Equation (3).…”

“…Previous studies used a similar approach employing grid cell theory or 3D‐RISM to account for the solvent perturbation upon ligand scaffold modifications . Changes in solvation energies can be used not only to rationalize differences in binding energies of chemically different ligands, but also for binding pose flips, as shown recently …”

“…[18,19] Changes in solvation energies can be used not only to rationalize differences in binding energies of chemically differentl igands,b ut also for binding pose flips,ass hown recently. [20] In the present study,w eu sed hydration site analysis( HSA) based on inhomogeneousf luid solvation theory (IFST) [21,22] to estimate binding site solvation free energies for congeneric ligand pairs at several receptors (Table 1). HSA in combination with IFST was applied before by Lazaridis to dissect the effect of water displacement on binding thermodynamics for conca-Computational methods, namely molecular dynamics (MD) simulations in combination with inhomogeneous fluid solvation theory (IFST) were used to retrospectively investigate various cases of ligand structure modificationst hat led to the displacemento fb inding site water molecules.…”

Structure‐Guided Synthesis and Evaluation of Small‐Molecule Inhibitors Targeting Protein–Protein Interactions of BRCA1 tBRCT Domain

“…The water molecules near to hydrophobic sites are entropically less stable. Therefore, in the conventional view, release of such unfavorable water to the bulk enhances ligand binding affinity . Study of stable waters at pockets has gained significant attention in recent years to design potent inhibitors and to understand binding mechanisms .…”

“…[21] Study of stable waters at pocketsh as gained significant attentioni nr ecent years to design potent inhibitors and to understand binding mechanisms. [21] Analysis of 23 BRCA1t BRCT crystal structures deposited in Protein Data Bank (www.rcsb.org) at the peptide binding site showedt wo possible rotomeric states of F1662. Therefore, to account for side chain flexibility,M Ds imulations were performedb yc onstraining only protein backbone and Ca atomso fa po BRCA1t BRCT,u nlike the conventional way where water thermodynamic analysis is generally done by harmonically restraining all protein atoms to their positions.…”