Molecular dynamics study of surface side chains in protein-ligand interactions

Protein-protein interactions play essential roles in cellular function. This study attempts to understand the biophysical basis underlying the recognition process in protein-ligand (protein-protein and protein-small molecule) interactions. Molecular dynamics (MD) simulations were performed on single proteins to analyze the flexibility and conformational distributions of surface residues. Analysis of the residue conformations on individual protein surfaces reveals a small subset of comparatively rigid residues on the surface of the free protein, "keys", in the center of the eventual interface, which could serve the recognition function by resembling the conformation found in the bound complex. The keys also provide the required affinity to hold the interacting proteins together to result in a productive complex. The existence of these keys implies that binding pathways can avoid kinetically costly structural rearrangements at the core of the binding interface, allowing for a relatively smooth and fast recognition process. These kinetically important key residues generally coincide with residues that are evolutionarily conserved and energetically important for complex formation. Similar residues that perform recognition functions are found in small-molecule binding pockets on protein surfaces. Docking studies confirm that side-chain optimization using solvated conformations obtained from MD analysis gives more near-native predictions than the unmodified structures of free proteins. Docking studies in protein-small-molecule binding indicate adaptive conformational changes (induced-fit) in a large fraction of the residues lining the ligand-binding site. From the MD analysis we also characterized the nature of interfaces and identified possible interface-like regions on protein surfaces.; Small-molecule ligand binding to protein surface pockets has been more difficult to predict because there are much more flexible adaptations involved in small molecule binding. To understand small-molecule ligand binding modes, we performed MD simulations on the protein with small organic solvents bound in the active site. The analysis helped to identify the origin and stability of weak, high-entropy binding interactions. The results from this study provide information about the probable ligand binding modes in the active sites of proteins and can be further applied to fragment-based drug design.