MD simulation study of several peptides including a polyalanine,a helix(pdb:2I9M),and a leucine zipper were carried out to investigate hydrogen bond energetics using dynamic polarized protein-specific charge(DPPC)to account for the polarization effect in protein dynamics.Results show that the backbone hydrogen-bond strength is generally correlated with its specific local electrostatic environment,measured by the number of water molecules near the hydrogen bond in the first solvation shell.The correlation coefficient is found to be 0.89,0.78,and 0.80,respectively,for polyalanine,2I9M protein,and leucine zipper.In the polyalanine,the energies of the backbone hydrogen bonds are very similar to each other due to their similar local electrostatic environment.The current study helps demonstrate and support the understanding that hydrogen bonds are stronger in a hydrophobic surrounding than in a hydrophilic one.For comparison,the result from simulation using standard force field shows a much weaker correlation between hydrogen bond energy and local electrostatic environment due to the lack of polarization effect in the force field.
DUAN Li LGAO YaJI Chang GMEI YeZHANG Qing GTANG BoZHANG John Z.H
The binding of Endonuclease colicin 9 (E9) by Immunity protein 9 (Im9) was found to involve some hotspots from helix III of Im9 on protein-protein interface that contribute the dominant binding energy to the complex.In the current work,MD simulations of the WT and three hotspot mutants (D51A,Y54A and Y55A of Im9) of the E9-Im9 complexes were carried out to investigate specific interaction mechanisms of these three hotspot residues.The changes of binding energy between the WT and mutants of the complex were computed by the MM/PBSA method using a polarized force field and were in excellent agreement with experiment values,verifying that these three residues were indeed hotspots of the binding complex.Energy decomposition analysis revealed that binding by D51 to E9 was dominated by electrostatic interaction due to the presence of the carboxyl group of Asp51 which hydrogen bonds to K89.For binding by hotspots Y54 and Y55,van der Waals interaction from the aromatic side chain of tyrosine provided the dominant interaction.For comparison,calculation by using the standard (nonpolarizable) AMBER99SB force field produced binding energy changes from these mutations in opposite direction to the experimental observation.Dynamic hydrogen bond analysis showed that conformations sampled from MD simulation in the standard AMBER force field were distorted from the native state and they disrupted the inter-protein hydrogen bond network of the protein-protein complex.The current work further demonstrated that electrostatic polarization plays a critical role in modulating protein-protein binding.
