Sulfur atoms have been known to participate in hydrogen bonds (H-bonds) and these sulfur-containing H-bonds (SCHBs) are suggested to play important roles in certain biological processes. This study aims to comprehensively characterize all the SCHBs in 500 high-resolution protein structures (< or =1.8 A). We categorized SCHBs into six types according to donor/acceptor behaviors and used explicit hydrogen approach to distinguish SCHBs from those of nonhydrogen bonding interactions. It is revealed that sulfur atom is a very poor H-bond acceptor, but a moderately good H-bond donor. In alpha-helix, considerable SCHBs were found between the sulphydryl group of cysteine residue i and the carbonyl oxygen of residue i-4, and these SCHBs exert effects in stabilizing helices. Although for other SCHBs, they possess no specific secondary structural preference, their geometric characteristics in proteins and in free small compounds are significantly distinct, indicating the protein SCHBs are geometrically distorted. Interestingly, sulfur atom in the disulfide bond tends to form bifurcated H-bond whereas in cysteine-cysteine pairs prefer to form dual H-bond. These special H-bonds remarkably boost the interaction between H-bond donor and acceptor. By oxidation/reduction manner, the mutual transformation between the dual H-bonds and disulfide bonds for cysteine-cysteine pairs can accurately adjust the structural stability and biological function of proteins in different environments. Furthermore, few loose H-bonds were observed to form between the sulphydryl groups and aromatic rings, and in these cases the donor H is almost over against the rim rather than the center of the aromatic ring.

Although fluorination of pharmacologically active compounds has long been a common strategy to increase their metabolic stability and membrane permeation, the functionality of protein-ligand interactions involving fluorine atoms (fluorine bonding) was only recently recognized in the chemistry and biology communities. In this study, the geometric characteristics and the energetic behaviors of fluorine bonding were systematically investigated by combining two quite disparate but complementary approaches: X-ray structural analysis and theoretical calculations. We found that the short contacts involving fluorine atoms (generalized fluorine bonding) between proteins and fluorinated ligands are very frequent, and these contacts, compared to those routine hydrogen/halogen bonding, are more similar to sulfur-involved hydrogen bonding observed in proteins. ONIOM-based quantum mechanics/molecular mechanics analysis further revealed that fluorine bonding does play an essential role in protein-ligand binding, albeit the strength of isolated fluorine bonding is quite modest. Furthermore, 14 quantum mechanics (QM) and molecular mechanics (MM) methods were performed to reproduce fluorine bonding energies obtained at the rigorous MP2/aug-cc-pVDZ level of theory, and the results showed that most QM and very few MM methods perform well in the reproducibility; the MPWLYP functional and MMFF94 force field are recommended to study moderate and large fluorine bonding systems, respectively.

BackgroundNoninvasive prenatal testing (NIPT) for fetal aneuploidies by scanning cell-free fetal DNA in maternal plasma is rapidly becoming a first-tier aneuploidy screening test in clinical practices. With the development of whole-genome sequencing technology, small subchromosomal deletions and duplications that could not be detected by conventional karyotyping are now able to be detected with NIPT technology.MethodsIn the present study, we examined 8141 single pregnancies with NIPT to calculate the positive predictive values of each of the chromosome aneuploidies and the subchromosomal microdeletions and microduplications.ResultsWe confirmed that the positive predictive values (PPV) for trisomy 13, trisomy 18, trisomy 21, and sex chromosome aneuploidy were 14.28%, 60%, 80%, and 45.83%, respectively. At the same time, we also found 51 (0.63%) positive cases for chromosomal microdeletions or microduplications but only 13 (36.11%) true-positive cases. These results indicate that NIPT for trisomy 21 detection had the highest accuracy, while accuracy was low for chromosomal microdeletion and microduplications.ConclusionsTherefore, it is very important to improve the specificity, accuracy, and sensitivity of NIPT technology for the detection of subchromosomal microdeletions and microduplications.

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Specific noncovalent interactions that are indicative of attractive, directional intermolecular forces have always been of key interest to medicinal chemists in their search for the "glue" that holds drugs and their targets together. With the rapid increase in the number of solved biomolecular structures as well as the performance enhancement of computer hardware and software in recent years, it is now possible to give more comprehensive insight into the geometrical characteristics and energetic landscape of certain sophisticated noncovalent interactions present at the binding interface of protein receptors and small ligands based on accumulated knowledge gaining from the combination of two quite disparate but complementary approaches: crystallographic data analysis and quantum-mechanical ab initio calculation. In this perspective, we survey massive body of published works relating to structural characterization and theoretical investigation of three kinds of strong, specific, direct, enthalpy-driven intermolecular forces, including hydrogen bond, halogen bond and salt bridge, involved in the formation of protein-ligand complex architecture in order to characterize their biological functions in conferring affinity and specificity for ligand recognition by host protein. In particular, the biomedical implications of raised knowledge are discussed with respect to potential applications in rational drug design.

A low molecular mass cutinase (designated TtcutA) from Thielavia terrestris was purified and biochemically characterized. The thermophilic fungus T. terrestris CAU709 secreted a highly active cutinase (90.4 U ml(-1)) in fermentation broth containing wheat bran as the carbon source. The cutinase was purified 19-fold with a recovery yield of 4.8 %. The molecular mass of the purified TtcutA was determined as 25.3 and 22.8 kDa using SDS-PAGE and gel filtration, respectively. TtcutA displayed optimal activity at pH 4.0 and 50 °C. It was highly stable up to 65 °C and in the broad pH range 2.5-10.5. Extreme stability in high concentrations (80 %, v/v) of solvents such as methanol, ethanol, acetone, acetonitrile, isopropanol, and dimethyl sulfoxide was observed for the enzyme. The K (m) values for this enzyme towards p-nitrophenyl (pNP) acetate, pNP butyrate, and pNP caproate were 7.7, 1.0, and 0.52 mM, respectively. TtcutA was able to efficiently degrade various ester polymers, including cutin, polyethylene terephthalate (PET), polycaprolactone (PCL), and poly(butylene succinate) (PBS) at hydrolytic rates of 3 μmol h(-1) mg(-1) protein, 1.1 mg h(-1) mg(-1) protein, 203.6 mg h(-1) mg(-1) protein, and 56.4 mg h(-1) mg(-1) protein, respectively. Because of these unique biochemical properties, TtcutA of T. terrestris may be useful in various industrial applications in the future.

In this paper, we have handpicked 23 kinds of electronic properties, 37 kinds of steric properties, 54 kinds of hydrophobic properties and 5 kinds of hydrogen bond properties from thousands of amino acid structural and property parameters. Principal component analysis (PCA) was applied on these parameters and thus ten score vectors involving significant nonbonding properties of 20 coded amino acids were yielded, called the divided physicochemical property scores (DPPS) of amino acids. The DPPS descriptor was then used to characterize the structures of 152 HLA-A*0201-restricted CTL epitopes, and significant variables being responsible for the binding affinities were selected by genetic algorithm, and a quantitative structure-activity relationship (QSAR) model by partial least square was established to predict the peptide-HLA-A*0201 molecule interactions. Statistical analysis on the resulted DPPS-based QSAR models were consistent well with experimental exhibits and molecular graphics display. Diversified properties of the different residues in binding peptides may contribute remarkable effect to the interactions between the HLA-A*0201 molecule and its peptide ligands. Particularly, hydrophobicity and hydrogen bond of anchor residues of peptides may have a significant contribution to the interactions. The results showed that DPPS can well represent the structural characteristics of the antigenic peptides and is a promising approach to predict the affinities of peptide binding to HLA-A*0201 in a efficient and intuitive way. We expect that this physical-principle based method can be applied to other protein-peptide interactions as well.