Solvent Sites Improve Docking Performance of Protein–Protein Complexes and Protein–Protein Interface-Targeted Drugs

Abstract

Protein–protein interactions (PPIs) are essential, and modulating their function through PPI-targeted drugs is an important research field. PPI sites are shallow protein surfaces readily accessible to the solvent, thus lacking a proper pocket to fit a drug, while their lack of endogenous ligands prevents drug design by chemical similarity. The development of PPI-blocking compounds is, therefore, a tough challenge. Mixed solvent molecular dynamics has been shown to reveal protein–ligand interaction hot spots in protein active sites by identifying solvent sites (SSs). Furthermore, our group has shown that SSs significantly improve protein–ligand docking. In the present work, we extend our analysis to PPI sites. In particular, we analyzed water, ethanol, and phenol-derived sites in terms of their capacity to predict protein–drug and protein–protein interactions. Subsequently, we show how this information can be incorporated to improve both protein–ligand and protein–protein docking. Finally, we highlight the presence of aromatic clusters as key elements of the corresponding interactions.

Hidden Markov Models based search in combination with structural bioinformatics pipeline leads to the identification of DAF-12 distant orthologous inMeloidogyne incognita

“…First, we estimated the predictive potential of phenol molecules to identify high occupancy regions in DAF-12 Sster and compare the key interactions with DAs-like compounds (S17 Fig) [15]. The two highly populated regions in the DAF-12 Sster binding site correlates with position of the aliphatic rings of the DA acids, validating the ability of phenol molecules for mapping hydrophobic interactions [19]. In the case of DAF-12 Minc , similar hotspots were found at the corresponding ligand binding site, indicating that despite the low correlation observed between the relevant residue position in the multiple alignments, the composition and spatial distribution of the amino acids could be sufficient to interact with the ligand.…”

“…Subsequently, we used Fpocket [18] to identify pockets that were consistent across the references and models (S2 Table ). Interestingly, all identified pockets were formed by a 3-layer α-helical sandwich-like array (S16 Fig) . Taking into account the DA ligands are mainly hydrophobic, we used molecular dynamics with mixed-solvents to obtain a detailed description of the potential protein-ligand interaction hotspot at the DAF12 binding site [19]. First, we estimated the predictive potential of phenol molecules to identify high occupancy regions in DAF-12 Sster and compare the key interactions with DAs-like compounds (S17 Fig) [15].…”

The Advances and Limitations of the Determination and Applications of Water Structure in Molecular Engineering

“…Thus, water molecules often play an important role in the ligand recognition and complex stabilization for nucleic acids, as well as proteins. There are several publications that have reported improvement in the success rate of the docking results when water molecules were included for RNA [191], DNA, and proteinprotein complexes [192,193]. However, due to their large, solvent-accessible interface, it is extremely challenging to incorporate water molecules into the process of docking macromolecules within a reasonable computation time.…”

Probing the conformational dynamics of an Ago–RNA complex in water/methanol solution

“…[21][22][23] For the oligonucleotide counterpart, a solvent with low polarity, can promote base pair opening 24 mainly due to the repulsion of the negative charge on a sugar phosphate backbone. In general, for protein complexes, computational studies such as molecular docking and molecular dynamics simulations performed in different solvents, can provide information related to specific site interactions between a protein and small ligand as well as protein and protein, particularly in the field of drug design [25][26][27] or to detect cryptic binding sites in proteins. [28][29][30] Considering protein RNA/DNA complexes, the role of aminoacids and nucleobases related to the strength of proteinoligonucleotide interactions, was also investigated using molecular dynamics simulations in methanol.…”