“Chameleonic” backbone hydrogen bonds in protein binding and as drug targets

Abstract

We carry out a time-averaged contact matrix study to reveal the existence of protein backbone hydrogen bonds (BHBs) whose net persistence in time differs markedly form their corresponding PDB-reported state. We term such interactions as "chameleonic" BHBs, CBHBs, precisely to account for their tendency to change the structural prescription of the PDB for the opposite bonding propensity in solution. We also find a significant enrichment of protein binding sites in CBHBs, relate them to local water exposure and analyze their behavior as ligand/drug targets. Thus, the dynamic analysis of hydrogen bond propensity might lay the foundations for new tools of interest in protein binding-site prediction and in lead optimization for drug design.

Hydrogen Bond Dynamic Propensity Studies for Protein Binding and Drug Design

“…However, our analysis is generally applicable to the protein-protein and drug-protein binding contexts. To study the dynamical behavior of these systems, as described in more detail in a previous work [11], were carried out molecular dynamics simulations by means of AMBER simulation package 14 [25], using in all cases periodic boundary conditions, TIP3P water and T = 300 K, always with the same minimization and equilibration protocol (equilibration was tested by monitoring the behavior of thermodynamical properties like temperature, pressure and energy oscillations). In the case of the MDM2-p53 complex (for the studies of the wild type complex and the computational alanine scanning studies) we performed production runs of 40 ns with 2 fs time step, recording 8000 equally spaced configurations.…”

“…As we have described in detail previously [11], the above expounded scenario is mainly rooted on structural facts while proteins are inherently dynamical objects and, thus, the structural information of the PDB, with the corresponding non-covalent interactions, might be veiling valuable information regarding protein interactions and function. In fact, we have shown that certain BHBs of apo proteins present a dynamic propensity (when studied in simulations that start form the PDB structure of the protein) that markedly differ from their corresponding PDB state-value [11].…”

“…In fact, we have shown that certain BHBs of apo proteins present a dynamic propensity (when studied in simulations that start form the PDB structure of the protein) that markedly differ from their corresponding PDB state-value [11]. That is, a few BHBs that are formed in the PDB of the apo protein display a conspicuous disruption tendency in the dynamics while, on the contrary, other BHBs are prominently formed in the protein dynamics while they are not established in the PDB structure [11].…”

“…In fact, we have shown that certain BHBs of apo proteins present a dynamic propensity (when studied in simulations that start form the PDB structure of the protein) that markedly differ from their corresponding PDB state-value [11]. That is, a few BHBs that are formed in the PDB of the apo protein display a conspicuous disruption tendency in the dynamics while, on the contrary, other BHBs are prominently formed in the protein dynamics while they are not established in the PDB structure [11]. We have also shown that protein binding sites are enriched in such “chameleonic'' BHBs (CBHBs, since they change state from the PDB prescription to the opposite formation propensity in solution), we have connected them to the binding-site hydration properties by means of water density fluctuation calculations (which estimate the work implied in water removal) and uncovered their role as drug targets [11].…”

“…That is, a few BHBs that are formed in the PDB of the apo protein display a conspicuous disruption tendency in the dynamics while, on the contrary, other BHBs are prominently formed in the protein dynamics while they are not established in the PDB structure [11]. We have also shown that protein binding sites are enriched in such “chameleonic'' BHBs (CBHBs, since they change state from the PDB prescription to the opposite formation propensity in solution), we have connected them to the binding-site hydration properties by means of water density fluctuation calculations (which estimate the work implied in water removal) and uncovered their role as drug targets [11]. This result puts the spotlight on chain dynamics and reveals backbone hydrogen bond dynamic propensity as a relevant tool for protein binding studies and drug design/optimization.…”