Systematic Interaction Analysis of Anti-Human Immunodeficiency Virus Type-1 Neutralizing Antibodies with High Mannose Glycans Using Fragment Molecular Orbital and Molecular Dynamics Methods.

A series of broadly neutralizing antibodies called PGT have been shown to be bound directly to human immunodeficiency virus type-1 via high mannose glycans on glycoprotein gp120. Despite the sequence similarities of amino acids of the antibodies, their affinities to the glycan differ. Glycan-antibody interactions among these antibodies are systematically compared with quantum chemical fragment molecular orbital calculations and molecular dynamics simulations. The differences among structural stability of the glycan in the active site of the complexes and total interaction energies as well as binding free energies between the glycan and antibodies agree well with the experimentally shown affinities of the glycan to the antibodies. The terminal saccharide, Man D3, is structurally stable and responsible for the glycan-antibody binding through electrostatic and dispersion interactions. The structural stability of nonterminal saccharides such as Man 4 or Man C plays substantial roles in the interaction via direct hydrogen bonds. © 2019 Wiley Periodicals, Inc.

Water molecules inside protein structure affect binding of monosaccharides with HIV-1 antibody 2G12.

Water molecules inside biomolecules constitute integral parts of their structure and participate in the functions of the proteins. Some of the X-ray crystallographic data are insufficient for analyzing a series of ligand-protein complexes in the same condition. We theoretically investigated antibody binding abilities of saccharide ligands and the effects of the inner water molecules of ligand-antibody complexes. Classical molecular dynamics and quantum chemical simulations using a model with possible water molecules inside the protein were performed with saccharide ligands and Human Immunodeficiency Virus 1 neutralizing antibody 2G12 complexes to estimate how inner water molecules of the protein affect the dynamics of the complexes as well as the ligand-antibody interaction. Our results indicate the fact that d-fructose's strong affinity to the antibody was partly due to the good retentiveness of solvent water molecules of the ligand and its stability of the ligand's conformation and relative position in the active site. © 2016 Wiley Periodicals, Inc.

Affinity of HIV-1 antibody 2G12 with monosaccharides: a theoretical study based on explicit and implicit water models.

In order to develop potential ligands to HIV-1 antibody 2G12 toward HIV-1 vaccine, binding mechanisms of the antibody 2G12 with the glycan ligand of D-mannose and D-fructose were theoretically examined. D-Fructose, whose molecular structure is slightly different from D-mannose, has experimentally shown to have stronger binding affinity to the antibody than that of D-mannose. To clarify the nature of D-fructose's higher binding affinity over D-mannose, we studied interaction between the monosaccharides and the antibody using ab initio fragment molecular orbital (FMO) method considering solvation effect as implicit model (FMO-PCM) as well as explicit water model. The calculated binding free energies of the glycans were qualitatively well consistent with the experimentally reported order of their affinities with the antibody 2G12. In addition, the FMO-PCM calculation elucidated the advantages of D-fructose over D-mannose in the solvation energy as well as the entropic contribution term obtained by MD simulations. The effects of explicit water molecules observed in the X-ray crystal structure were also scrutinized by means of FMO methods. Significant pair interaction energies among D-fructose, amino acids, and water molecules were uncovered, which indicated contributions from the water molecules to the strong binding ability of D-fructose to the antibody 2G12. These FMO calculation results of explicit water model as well as implicit water model indicated that the strong binding of D-fructose over D-mannose was due to the solvation effects on the D-fructose interaction energy.

A theoretical study of the physicochemical mechanisms associated with DNA recognition modulation in artificial zinc-finger proteins.

The DNA-binding ability of the zinc-finger (ZF) protein and the modulation of its affinity to DNA through amino acid mutations were theoretically investigated. Classical molecular dynamics and energy decomposition analysis based on large-scale ab initio fragment molecular orbital calculations were used to obtain the DNA binding affinities of wild-type and three mutant ZFs. Calculated binding free energies qualitatively well explained the DNA binding affinity modulation experimentally observed by Dhanasekaran et al. [Dhanasekaran, M.; et al., Biochemistry 2007, 46, 7506-7513]. It had been considered that only the α-helix domain in the ZF plays an important role in DNA recognition; however, our results clearly show that the N-terminal regions, BR1 and BR2, also play important roles in DNA recognition.

Computational studies of gas-phase Ca3P2 and Ca6P4.

The electronic and molecular structures of Ca3P2 and Ca6P4 are investigated using high-level ab initio methods. The lowest energy structure for Ca3P2 is found to be a Jahn-Teller distorted triplet. An excited-state singlet is found with various post HF methods; however, DFT incorrectly predicts a closed shell singlet to be the ground state. For the Ca6P4 system, both DFT and ab initio methods give consistent relative energies. The computational results demonstrate that the energetics are very sensitive to the size of the Ca basis set. Enhancing the Ca basis sets with additional s and p valence functions significantly affects the calculated energies.

Recognition of tandem sialic acid residues by CD38: a theoretical study.

The electronic structures of gangliosides are described using semiempirical and ab inito molecular orbital theories as well as the density functional theory to clarify the causative factors of the differences in inhibitory effects and to elucidate the recognition mechanisms of the enzyme. Our results suggest that CD38 is likely to recognize the two phosphate groups in NAD and the two carboxyl groups in tandem sialic acid residues of gangliosides. The recognition mechanisms of the substrate are proposed based on the good correlation found between the orbital energy of the highest occupied molecular orbital of the gangliosides and the degree of the inhibitory effect.

Density functional study of the structures of lead sulfide clusters (PbS)n (n = 1-9).

The structures of (PbS)n (n = 1-9) clusters are investigated with density functional theory at the B3LYP level. Various pseudopotential basis sets on lead and the 6-31+G basis set on sulfur were employed. Full geometry optimization and extensive searches of the potential energy surface were carried out for clusters with n = 1-6. We find that even small PbS clusters (n > 2) start to take on the characteristic features of the rock salt structure of solid-state PbS (galena). The origin of some of the structural aspects of these crystals is shown to be associated with the partial covalent nature of the Pb-S bond. The magnitude of the HOMO-LUMO gap oscillates with increasing size of the clusters, in agreement with the observed behavior of the corresponding UV absorption bands of ultrasmall PbS quantum dots. Direct conformation of this oscillation was found by CIS(D) calculations, for which the absorption with the largest oscillator strength oscillates as the clusters grow from PbS to (PbS)9.

Novel sulfated gangliosides, high-affinity ligands for neural siglecs, inhibit NADase activity of leukocyte cell surface antigen CD38.

Three kinds of novel sulfated gangliosides structurally related to the Chol-1 (alpha-series) ganglioside GQ1balpha were synthesized. These sulfated gangliosides were potent inhibitors of NADase activity of leukocyte cell surface antigen CD38. Among the synthetic gangliosides, GSC-338 (II(3)III(6)-disulfate of iso-GM1b) was surprisingly found to be the most potent structure in both the NADase inhibition and MAG-binding activity. The present study indicates that the sulfated gangliosides are useful to study the recognition of the internal tandem sialic acid residues alpha2-3-linked to Gal(II(3)) as well as the siglec-dependent recognition including a terminal sialic acid residue.