A new peptide modification strategy was recently developed to replace the i to i + 4 hydrogen bond of the main chain of an alpha-helix with a carbon-carbon covalent bond to afford highly stable constrained alpha-helices, termed hydrogen-bond surrogate (HBS) helices. HBS helices that mimic the Bak BH3 domains were experimentally demonstrated to target protein Bcl-x(L) with high affinity. In this study, molecular dynamics (MD) simulation is used to understand how the covalent modification of the natural Bak sequence affects the binding to Bcl-x(L) at molecular levels. The binding mechanism of HBS helix to Bcl-x(L) and the effect of synthesized cyclic structures are analyzed by MD and MM-PBSA calculations for comparison with the native binding of Bak-Bcl-x(L). The present MD result shows that the entropy of the HBS structure is considerably reduced, and the presence of the N-terminal HBS macrocycle impacts residues at the C-terminus of the helix, but the conformation of the corresponding binding structures is not significantly changed. Our analysis shows that substitution of an aspartic acid residue-a helix breaker-with a hydrophobic residue not only enhances the helicity of the peptide but also stabilizes the structure of the binding complex. The present computational result is consistent with the experimental observation and provides explanations for the altered binding properties of the artificial Bak alpha-helix. Our study underscores the importance of the dynamical effect in protein-peptide interaction in which entropic effect plays a major role.