Theoretical Studies of Interactions between O-Phosphorylated and Standard Amino-Acid Side-Chain Models in Water

Abstract

Phosphorylation is a common post-translational modification of the amino-acid side chains (serine, tyrosine, and threonine) that contain hydroxyl groups. The transfer of the negatively charged phosphate group from an ATP molecule to such amino-acid side chains leads to changes in the local conformations of proteins and the pattern of interactions with other amino-acid side-chains. A convenient characteristic of the side chain–side chain interactions in the context of an aqueous environment is the potential of mean force (PMF) in water. A series of umbrella-sampling molecular dynamic (MD) simulations with the AMBER force field were carried out for pairs of O-phosphorylated serine (pSer), threonine (pThr), and tyrosine, (pTyr) with natural amino acids in a TIP3P water model as a solvent at 298 K. The weighted-histogram analysis method was used to calculate the four-dimensional potentials of mean force. The results demonstrate that the positions and depths of the contact minima and the positions and heights of the desolvation maxima, including their dependence on the relative orientation depend on the character of the interacting pairs. More distinct minima are observed for oppositely charged pairs such as, e.g., O-phosphorylated side-chains and positively charged ones, such as the side-chains of lysine and arginine.

Introduction of Phosphorylated Residues into the UNRES Coarse-Grained Model: Toward Modeling of Signaling Processes

“…The fitted parameters for both variants of the potentials are collected in Table S1 of the Supporting Information. Sample plots of the fitted potential curves and the respective PMFs (determined in ref ) for selected orientations, which are depicted in Figure , are shown in Figures and for the minimalistic and extended force-field variant, respectively, while the plots of all potentials superposed on the PMFs are shown in Figure S3 (left panels) of the Supporting Information.…”

“…We extended the physics-based coarse-grained UNRES model of polypeptide chains to include phosphorylated amino-acid residues. Analytical functions of two types, one minimalistic and one including the Debye–Hückel correction of the solvent polarization term, were fitted to the potentials of mean force of phosphorylated amino-acid residues determined in our previous study . The energy functions along with parameters were implemented in UNRES.…”

“…The parameters of the expressions for the potentials involving the phosphorylated side chains were determined by fitting them to the respective potentials of mean force determined in ref using Marquardt’s algorithm of nonlinear regression . The data points corresponding to all distances and orientations were taken.…”

“…In this work, we propose an extension of the physics-based UNRES − coarse-grained model of polypeptide chains developed in our laboratory to include phosphorylated amino-acid residues. To determine the respective potentials, we fitted the appropriate physics-based analytical expressions constructed based on our earlier work to the potentials of mean force derived from pairs composed of models of phosphorylated and regular amino-acid residues determined earlier . The new potentials were subsequently introduced into UNRES and tested with two miniproteins containing phosphorylated residues.…”

“…To determine the respective potentials, we fitted the appropriate physics-based analytical expressions constructed based on our earlier work 32 to the potentials of mean force derived from pairs composed of models of phosphorylated and regular amino-acid residues determined earlier. 33 The new potentials were subsequently introduced into UNRES and tested with two miniproteins containing phosphorylated residues. ■ METHODS UNRES Model of Polypeptide Chains.…”