Narrow Results

Using N-Methylacetamide (NMA) dimer and NMA–water as model complexes, the solvent effect on the protein inter- N–H⋯O=C and intra- N –H⋯OH₂, and C=O⋯H₂O hydrogen bonding have been studied by the polarizable continuum model (PCM) ab initio calculations in the four media (vacuum, ether, nitromethane and water). In contrast to the empirical approaches, we suggested using the direction interaction energies (DE) to consider the solvent polarization, which can be derived from PCM ab initio calculations. The DEs of the model compounds in solvents are larger than their in vacuo binding energies, which reflect the solvent polarization effect. As the solvents become increasingly polar, the binding free energies decrease while DEs increase. The increasing DE is consistent with the increasing hydrogen bond length. Considering the protein environment, the DEs of NMA-NMA dimer in ether, 9.14 and 9.41 kcal/mol for NMADI and NMADII, are recommended for the intra N–H⋯O=C hydrogen bonding. The DEs of NMA–water complex in water, -5.47 (NMAWI) and -5.41 kcal/mol (NMAWI'), -8.44 (NMAWII) and -8.68 kcal/mol (NMAWII'), respectively, are suggested for the inter- N–H⋯OH₂ and C–O⋯H₂O hydrogen bonding of proteins. Using the same approach, we have also computed the DE of water dimer in liquid water. The computed DE of water dimer (-5.63 kcal/mol) is larger than the in vacuo water dimerization energy (-5.14 kcal/mol) and in reasonable agreement with the dimerization energies (ranging from –6.0 to 6.8 kcal/mol) of polarization-included empirical water models.

The conformational preferences of peptide models have been investigated to understand the protein folding mechanism and to develop the force field. Here, we report the minimum energy conformations for a model peptide, N-acetyl–glycine–glycine–N′-methylamide (Ac–¹Gly–²Gly–NHMe(I)) at the HF/3-21G, HF/6-31G*, and the B3LYP/6-31G* level of theory. At the B3LYP/6-31G* level, the 31 minima were identified and the 10 β-turn structures among the minima were observed in gas-phase. The conformational preferences of Gly residue in the model peptide, I depend on its relative position and conformation of neighboring Gly residue. The Gly residue in this model dipeptide has an asymmetric energy profile as one of Gly residue adopts a specific conformation. This study sheds some lights on understanding the unique conformational preferences of Gly residue in protein including two consecutive Gly residues.

Protein kinase C isoform $\iota$ (PKC$\iota )$ is an essential regulator of diverse neurobiological signaling pathways, which has been implicated in general anesthetic action and a variety of nervous neoplasms. Traditional efforts have been primarily addressed on the development of small-molecule inhibitors to target the catalytic or regulatory domain of this kinase. Instead, we herein reported a rational chemical modification of Par3 pseudosubstrate peptide to target the kinase domain with improved affinity and specificity. Structural and energetic analysis suggested that the Par3 peptide can be divided into two binding-independent sections; they are separately anchored to the substrate-binding pocket of PKC$\iota$ with two aromatic anchor residues Phe818 and Phe823. The side-chain phenyl group of these two aromatic residues was systematically substituted by different halogen moieties at $o$-, $m$- and $p$-positions of the phenyl group. It is revealed that the $p$-bromination of Par3 Phe818 and the $p$-iodinization of Par3 Phe823 residue can separately form two geometrically and energetically satisfactory orthogonal halogen (X)-bond/hydrogen (H)-bond [ortX/H] motifs across Par3 complex interface with PKC$\iota$; they co-define a so-called ortX/H system and were demonstrated to improve both the binding affinity and recognition specificity of the kinase–peptide interaction by integrating in silico analysis and in vitro assay. The peptide affinity promotes 23.5-fold and 6.6-fold upon the formation of ortX/H motif-I and motif-II, respectively, which further increases to 43.5-fold by forming the complete ortX/H system, indicating cooperativity between the two motifs in the system. In addition, we also demonstrated that the ortX/H system can considerably enhance the peptide selectivity for its cognate PKC$\iota$ and noncogante isoforms PKC$\alpha$ and PKC$\delta$.