Hydrogen Bond Strengths in Phosphorylated and Sulfated Amino Acid Residues

<div><p>Post-translational modification by the addition of an oxoanion functional group, usually a phosphate group and less commonly a sulfate group, leads to diverse structural and functional consequences in protein systems. Building upon previous studies of the phosphoserine residue (pSer), we address the distinct nature of hydrogen bonding interactions in phosphotyrosine (pTyr) and sulfotyrosine (sTyr) residues. We derive partial charges for these modified residues and then study them in the context of molecular dynamics simulation of model tripeptides and sulfated protein complexes, potentials of mean force for interacting residue pairs, and a survey of the interactions of modified residues among experimental protein structures. Overall, our findings show that for pTyr, bidentate interactions with Arg are particularly dominant, as has been previously demonstrated for pSer. sTyr interactions with Arg are significantly weaker, even as compared to the same interactions made by the Glu residue. Our work sheds light on the distinct nature of these modified tyrosine residues, and provides a physical-chemical foundation for future studies with the goal of understanding their roles in systems of biological interest.</p> </div

Percentage of Glu, pSer, pTyr and sTyr residues showing a given number of hydrogen bonds.

<p>Residues were drawn from all structures in the Protein Databank containing a pSer, pTyr, or sTyr residue. For Glu, residues were taken from the set of structures containing a pSer residue.</p

A comparison of electrostatic potentials for sTyr, pTyr(−1), and pTyr(−2).

<p>Electrostatic potentials are shown at isosurfaces of +/−2 kTe. The protonated phosphate group of pTyr(−1) presents a shaped charge that can provide a stronger interaction with hydrogen bond donors than the more isotropic charge on the sTyr sulfate.</p

Hydrogen Bond Occupancies in Molecular Dynamics Simulation of Tripeptide Systems.

<p>Columns report the percentage of frames showing a particular hydrogen bond for tripeptides Xxx-Gly-Yyy where Xxx represents hydrogen bonding donors Arg, Lys, or Gln; and Yyy represents Glu, pSer(−2), pSer(−1), pTyr(−2), pTyr(−1), or sTyr. For Arg tripeptides, the table reports percentages for single and bidentate interactions.</p

Characterization of Hydrogen Bonds to Glu, pSer, pTyr, and sTyr in Experimental Protein Structures.

<p>Columns report the percentage of hydrogen bonds to Glu, pSer, pTyr or sTyr, that are to a given donor residue, and for Arg in a single or bidentate orientation. Residues were drawn from all structures in the Protein Databank containing a pSer, pTyr, or sTyr residue. For Glu, residues were taken from the set of structures containing a pSer residue.</p

Implicit Solvent Potentials of Mean Force for representative residue pairs.

<p>Plots show interaction energy vs. distance, at distance intervals of 0.25 Å, for a pair of residues in a given orientation. Distance refers to the P-C distance between the phosphate atom and the terminal carbon on Arg (coplanar), or the N-O distance (collinear).</p

Ensemble- and Rigidity Theory-Based Perturbation Approach To Analyze Dynamic Allostery

Allostery describes the functional coupling between sites in biomolecules. Recently, the role of changes in protein dynamics for allosteric communication has been highlighted. A quantitative and predictive description of allostery is fundamental for understanding biological processes. Here, we integrate an ensemble-based perturbation approach with the analysis of biomolecular rigidity and flexibility to construct a model of dynamic allostery. Our model, by definition, excludes the possibility of conformational changes, evaluates static, not dynamic, properties of molecular systems, and describes allosteric effects due to ligand binding in terms of a novel free-energy measure. We validated our model on three distinct biomolecular systems: eglin c, protein tyrosine phosphatase 1B, and the lymphocyte function-associated antigen 1 domain. In all cases, it successfully identified key residues for signal transmission in very good agreement with the experiment. It correctly and quantitatively discriminated between positively or negatively cooperative effects for one of the systems. Our model should be a promising tool for the rational discovery of novel allosteric drugs

The structural and energetic properties of six predetermined models through 10 ns MD simulation.

<p>The interaction energy is accounting the interaction energy between the kinase and pseudokinase domain. PK_RMSF is the RMSF of Cα atom of JH2 after superimposing on kinase domain in MD simulation. BSA is the buried surface areas and H/I are contacts between the hydrophobic residues within 5 Å and charged residues within 6 Å in the interfaces. KH_RMSF is the RMSF of Cα atom in kinase αC helix (residues 885 to 907) after superimposing on kinase domain in MD simulation.</p

JAK2 JH1-JH2 complex model involves two sets of significant interfacial residues.

<p>The JH2 (residues 523 to 816) is shown in blue cartoon while the kinase domain (residues 840 to 1132) is shown in yellow cartoon. The linker loop between two domains is colored pink. Interface 1 shows a site of electrostatic complementarity near the αC helix region of the JH2 and the αEF/αF loop region of kinase domain. The electrostatic complementarity is provided by R588, E592, E1028 and K1030. Interface 2 is composed of mainly hydrophobic residues, especially V706, L707, I901, R971, I973 and V1033.</p

Model for the calculation of local volume fraction for the sphere i.

<p>In this model, R_cut is 4 times radius of central sphere i, and j and k are spheres that lie completely inside and partially inside R_cut, respectively.</p