Phosphorylation Effects on cis/trans Isomerization and the Backbone Conformation of Serine−Proline Motifs:  Accelerated Molecular Dynamics Analysis

The presence of serine/threonine−proline motifs in proteins provides a conformational switching mechanism of the backbone through the cis/trans isomerization of the peptidyl−prolyl (ω) bond. The reversible phosphorylation of the serine/threonine modulates this switching in regulatory proteins to alter signaling and transcription. However, the mechanism is not well understood. This is partly because cis/trans isomerization is a very slow process and, hence, difficult to study. We have used our accelerated molecular dynamics method to study the cis/trans proline isomerization, preferred backbone conformation of a serine−proline motif, and the effects of phosphorylation of the serine residue. We demonstrate that, unlike normal molecular dynamics, the accelerated molecular dynamics allows for the system to escape very easily from the trans isomer to cis isomer, and vice versa. Moreover, for both the unphosphorylated and phosphorylated peptides, the statistical thermodynamic properties are recaptured, and the results are consistent with experimental values. Isomerization of the proline ω bond is shown to be asymmetric and strongly dependent on the ψ backbone angle before and after phosphorylation. The rates of escape decrease after phosphorylation. Also, the α-helical backbone conformation is more favored after phosphorylation. This accelerated molecular dynamics approach provides a general approach for enhancing the conformational transitions of molecular systems without having prior knowledge of the location of the minima and barriers on the potential-energy landscape.