Theoretical Study of the Free Energy Surface and Kinetics of the Hepatitis C Virus NS3/NS4A Serine Protease Reaction with the NS5A/5B Substrate. Does the Generally Accepted Tetrahedral Intermediate Really Exist?

ACS Catalysis
The self-consistent charge density functional tight binding/molecular mechanics (SCC-DFTB/MM) and ensemble averaged variational transition state theory/multidimensional tunneling (EA-VTST/MT) methods have been employed to investigate the reaction mechanism and to calculate the rate constant of the NS3/NS4A + NS5A/5B acylation reaction. This reaction belongs to the vital cycle of the hepatitis C virus once it infects the human cell. A concerted reaction mechanism, with a single transition state in which the tetrahedral geometry has already been adopted and the peptide bond is starting to break, has been determined. This reaction supposes an example where the proposed general two-step serine protease acylation reaction mechanism does not occur, being related to the fact that the enzyme is particularly efficient for the NS5A/5B substrate. The transition state characterized here for the acylation reaction can be a good initial structure in the reach of NS3/NS4A inhibitors based on TS...  Read more

Carbon nanoscroll from C4H/C4F-type graphene superlattice: MD and MM simulation insights

Physical Chemistry Chemical Physics
Morphology manipulation opens up a new avenue for controlling and tailoring the functional properties of graphene, enabling the exploration of graphene-based nanomaterials. Through mixing single-side-hydrogenated graphene (C4H) with fluorinated graphene (C4F) on one single sheet, the C4H/C4F-type graphene superlattices can self-scroll at room temperature. We demonstrate using molecular dynamic (MD) simulations that different proportions, sizes, directions of hydrogenation and fluorination, and geometry of graphene have a great influence on the self-scrolling of superlattices into a variety of well-defined carbon nanoscrolls (CNSs), thus providing a controllable approach to tune their structures. Based on molecular mechanics (MM) simulations, the CNSs bear more than eight times the radial pressure than that of their multiwalled carbon nanotube (MWNT) counterparts, and an excellent...  Read more

Gold finger formation studied by high-resolution mass spectrometry and in silico methods

Chemical Communications
High-resolution mass spectrometry and quantum mechanics/molecular mechanics studies were employed for characterizing the formation of two gold finger (GF) domains from the reaction of zinc fingers (ZF) with gold complexes. The influence of both the gold oxidation state and the ZF coordination sphere in GF formation provided useful insights into the possible design of new gold complexes targeting specific ZF motifs.Read more

Differential structural dynamics and antigenicity of two similar influenza H5N1 virus HA-specific HLA-A*0201-restricted CLT epitopes

RSC Advances
The presentation of viral peptides by major histocompatibility complex (MHC) molecules for T cell receptor (TCR) recognition is the central event in the development of T cell immunity against viruses. Molecular dynamics (MD) simulation is a powerful tool that is able to provide dynamic information, rather than a static view, of the mechanisms of peptide presentation in the antigen binding grooves of MHCs. In this paper, MD simulations are presented for two influenza H5N1 virus HA-specific cytotoxic T lymphocyte (CTL) epitopes, RI-10 (RLYQNPTTYI) and KI-10 (KLYQNPTTYI), in complex with HLA-A*0201. Although the amino acid sequence difference between RI-10 and KI-10 is slight, the structural dynamics of the two peptides were found to differ substantially. Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) calculations, and the thermal stability of the two complexes determined from their circular dichroism (CD) spectra, suggested that RI-10 had a higher binding free energy to...  Read more

High affinity of p-sulfonatothiacalix[4]arene with phenanthroline-diium in aqueous solution

RSC Advances
The molecular binding behavior of three sulfonated calixarene hosts, p-sulfonatocalix[4]arene (SC4A), p-sulfonatocalix[5]arene (SC5A), and p-sulfonatothiacalix[4]arene (STC4A), with two phenanthroline-diium guests, 5,6-dihydropyrazion[1,2,3,4-lmn][1,10]phenanthroline-4,7-diium (DP2+) and 6,7-dihydro-5H-[1,4]diazepino[1,2,3,4-lmn][1,10]phenanthroline-4,8-diium (PPQ2+), were systemically investigated in neutral phosphate buffer solutions by microcalorimetry, cyclic voltammetry, NMR spectroscopy, and molecular mechanics calculation. We found that the phenanthroline-diium guests were captured by SC4A, SC5A, and STC4A from their aromatic moieties. Furthermore, STC4A displays a high affinity with phenanthroline-diium guests in the order of magnitude of 105 M−1. It is the reported highest binding order of magnitude for STC4A up to...  Read more

Molecular modelling studies of sirtuin 2 inhibitors using three-dimensional structure–activity relationship analysis and molecular dynamics simulations

Molecular BioSystems
Sirtuin 2 (SIRT2) is a nicotinamide-adenine-dinucleotide-dependent histone deacetylase that plays a vital role in various biological processes related to DNA regulation, metabolism, and longevity. Recent studies on SIRT2 have indicated its therapeutic potential for neurodegenerative diseases such as Parkinson's disease. In this study, a series of SIRT2 inhibitors with a 2-anilinobenzamide core was analysed using a combination of molecular modelling techniques. A three-dimensional structure–activity relationship (3D-QSAR) model adopting a comparative molecular field analysis (CoMFA) method with a non-cross-validated correlation coefficient R2 = 0.992 (for training set) and a correlation coefficient Rtest2 = 0.804 (for test set) was generated to determine the structural requirements for inhibitory activity. Furthermore, we employed molecular dynamics (MD) simulations and the molecular...  Read more

Improving the Q2MM method for transition state force field modeling

Journal of Computational Chemistry
The Quantum-to-molecular mechanics method (Q2MM) for converting quantum mechanical transition states (TSs) to molecular mechanical minima has been modified to allow a fit to the “natural” reaction mode eigenvalue. The resulting force field gives an improved representation of the energy curvature at the TS, but can potentially give false responses to steric interactions. Ways to address this problem while staying close to the “natural” TS force field are discussed. Read more

Including Thermal Disorder of Hydrogen Bonding to Describe the Vibrational Circular Dichroism Spectrum of Zwitterionic l-Alanine in Water

The Journal of Physical Chemistry A
The vibrational circular dichroism (VCD) spectrum of l-alanine amino acid in aqueous solution in ambient conditions has been studied. The emphasis has been placed on the inclusion of the thermal disorder of the solute–solvent hydrogen bonds that characterize the aqueous solution condition. A combined and sequential use of molecular mechanics and quantum mechanics was adopted. To calculate the average VCD spectrum, the DFT B3LYP/6-311++G(d,p) level of calculation was employed, over one-hundred configurations composed of the solute plus all water molecules making hydrogen bonds with the solute. Simplified considerations including only four explicit solvent molecules and the polarizable continuum model were also made for comparison. Considering the large number of vibration frequencies with only limited experimental results a direct comparison is presented, when possible, and in addition a statistical analysis of the calculated values was performed. The...  Read more

Vibrational Circular Dichroism and Theoretical Study of the Conformational Equilibrium in (−)‐S‐Nicotine

We report an extensive study of the molecular and electronic structure of (−)-S-nicotine, to deduce the phenomenon that controls its conformational equilibrium and to solve its solution-state conformer population. Density functional theory, ab initio, and molecular mechanics calculations were used together with vibrational circular dichroism (VCD) and Fourier transform infrared spectroscopies. Calculations and experiments in solution show that the structure and the conformational energy profile of (−)-S-nicotine are not strongly dependent on the medium, thus suggesting that the conformational equilibrium is dominated by hyperconjugative interactions rather than repulsive electronic effects. The analysis of the first recorded VCD spectra of (−)-S-nicotine confirmed the presence of two main conformers at room temperature. Our results provide further evidence of the hypersensitivity of vibrational optical activity spectroscopies to the three-dimensional...  Read more

Toward Fully Nonempirical Simulations of Optical Band Shapes of Molecules in Solution: A Case Study of Heterocyclic Ketoimine Difluoroborates

The Journal of Physical Chemistry A
This study demonstrates that a hybrid density functional theory/molecular mechanics approach can be successfully combined with time-dependent wavepacket approach to predict the shape of optical bands for molecules in solutions, including vibrational fine structure. A key step in this treatment is the estimation of the inhomogeneous broadening based on the hybrid approach, where the polarization between solute and atomically decomposed solvent is taken into account in a self-consistent manner. The potential of this approach is shown by predicting optical absorption bands for three heterocyclic ketoimine difluoroborates in solution.Read more

Molecular recognition of upper rim functionalized cavitand and its unique dimeric capsule in the solid state

Organic & Biomolecular Chemistry
Cavitand 1 possesses four 2,2′-bipyridyl pillars on its upper rim that encapsulates small guests, such as nitromethane, acetonitrile, methyl acetate, ethyl acetate, and N-methylacetamide, into a deep cavity to form host–guest complexes in a 1 : 1 ratio. Nitroethane, N,N-dimethylformamide, and N,N-dimethylacetamide were not bound in this manner. A guest-binding study and molecular mechanics calculations revealed that the four 2,2′-bipyridyl pillars of cavitand 1 created a steric boundary that is responsible for selective guest recognition. In the solid state, cavitand 2 formed a unique chiral capsule 22 by π–π stacking interactions between the 2,2′-bipyridyl pillars. A nitromethane...  Read more

Could the “Janus‐like” properties of the halobenzene CX bond (XCl, Br) be leveraged to enhance molecular recognition?

Journal of Computational Chemistry
The CX bond in halobenzenes (X[DOUBLE BOND]Cl, Br) exhibits a dual character, being electron-deficient along the CX direction, and electron-rich on its flanks. We sought to amplify both features by resorting to electron-withdrawing and electron-donating substituents, respectively. This was done by quantum chemistry (QC) computations in the recognition sites of three protein targets: farnesyl transferase, coagulation factor Xa, and the HIV-1 integrase. In this context, some substituents, notably fluorine, CF3, and NHCH3, afforded significant overall gains in the binding energies as compared to the parent halobenzene, in the 2–5 kcal/mol range. In fact, we found that some di- and up to tetra-substitutions enabled even larger gains than those they contribute separately owing to many-body effects. Moreover, desolvation was also found to be a key contributor to the energy...  Read more

Optical Signature of Formation of Protein Corona in the Firefly Luciferase-CdSe Quantum Dot Complex

Journal of Chemical Theory and Computation
Theoretical investigation of protein corona is challenging because of the size of the protein-dot complex. In this work, we have addressed this computational bottleneck by combining pseudopotential + explicitly correlated Hartree–Fock QM calculations with molecular mechanics, molecular dynamics, and Monte Carlo techniques. The optical gap of a 5 nm CdSe quantum dot (Cd1159Se1183) was computed by sequential addition of luciferase (Lu), and a red shift of 8 nm in the λmax of protein corona (CdSe–Lu7) was observed.Read more

Wetting of water on hexagonal boron nitride@Rh(111): a QM/MM model based on atomic charges derived for nano-structured substrates

Physical Chemistry Chemical Physics
The wetting of water on corrugated and flat hexagonal boron nitride (h-BN) monolayers on Rh(111) is studied within a hybrid quantum mechanics/molecular mechanics (QM/MM) approach. Water is treated by QM methods, whereas the interactions between liquid and substrate are described at the MM level. The electrostatic properties of the substrate are reproduced by assigning specifically generated partial charges to each MM atom. We propose a method to determine restrained electrostatic potential (RESP) charges that can be applied to periodic systems. Our approach is based on the Gaussian and plane waves algorithm and allows an easy tuning of charges for nano-structured substrates. We have successfully applied it to reproduce the electrostatic potential of the corrugated and flat h-BN/Rh(111) known as nanomesh. Molecular dynamics simulations of water films in contact with these substrates are performed and structural and dynamic properties of the interfaces are analyzed. Based on this...  Read more

Structure of Framework Aluminum Lewis Sites and Perturbed Aluminum Atoms in Zeolites as Determined by 27Al{1H} REDOR (3Q) MAS NMR Spectroscopy and DFT/Molecular Mechanics

Angewandte Chemie International Edition
Zeolites are highly important heterogeneous catalysts. Besides Brønsted SiOHAl acid sites, also framework AlFR Lewis acid sites are often found in their H-forms. The formation of AlFR Lewis sites in zeolites is a key issue regarding their selectivity in acid-catalyzed reactions. The local structures of AlFR Lewis sites in dehydrated zeolites and their precursors—“perturbed” AlFR atoms in hydrated zeolites—were studied by high-resolution MAS NMR and FTIR spectroscopy and DFT/MM calculations. Perturbed framework Al atoms correspond to (SiO)3AlOH groups and are characterized by a broad 27Al NMR resonance (δi=59–62 ppm, CQ=5 MHz, and η=0.3–0.4) with a shoulder at 40 ppm in the 27Al MAS NMR spectrum. Dehydroxylation of (SiO)3AlOH occurs at mild temperatures and leads to the formation of AlFR Lewis sites tricoordinated...  Read more

Free Energy Simulations of Active-Site Mutants of Dihydrofolate Reductase

The Journal of Physical Chemistry B
This study employs hybrid quantum mechanics–molecular mechanics (QM/MM) simulations to investigate the effect of mutations of the active-site residue I14 of E. coli dihydrofolate reductase (DHFR) on the hydride transfer. Recent kinetic measurements of the I14X mutants (X = V, A, and G) indicated slower hydride transfer rates and increasingly temperature-dependent kinetic isotope effects (KIEs) with systematic reduction of the I14 side chain. The QM/MM simulations show that when the original isoleucine residue is substituted in silico by valine, alanine, or glycine (I14V, I14A, and I14G DHFR, respectively), the free energy barrier height of the hydride transfer reaction increases relative to the wild-type enzyme. These trends are in line with the single-turnover rate measurements reported for these systems. In addition, extended dynamics simulations of the reactive Michaelis complex reveal enhanced flexibility in the mutants, and in particular for the I14G mutant, including...  Read more

Ab Initio QM/MM Study Shows a Highly Dissociated SN2 Hydrolysis Mechanism for the cGMP-Specific Phosphodiesterase-5

Journal of Chemical Theory and Computation
Phosphodiesterases (PDEs) are the sole enzymes hydrolyzing the important second messengers cGMP and cAMP and have been identified as therapeutic targets for several diseases. The most successful examples are PDE5 inhibitors (i.e., sildenafil and tadalafil), which have been approved for the treatment of male erectile dysfunction and pulmonary hypertension. However, the side effects mostly due to nonselective inhibition toward other PDE isoforms, set back the clinical usage of PDE5 inhibitors. Until now, the exact catalytic mechanism of the substrate cGMP by PDE5 is still unclear. Herein, the first computational study on the catalytic hydrolysis mechanism of cGMP for PDE5 (catalytic domain) is performed by employing the state-of-the-art ab initio quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations. Our simulations show a SN2 type reaction procedure via a highly dissociated transition state with a reaction barrier of 8.88 kcal/mol, which is quite...  Read more

Exploration of the Zinc Finger Motif in Controlling Activity of Matrix Metalloproteinases

The Journal of Physical Chemistry B
Discovering ways to control the activity of matrix metalloproteinases (MMPs), zinc-dependent enzymes capable of degrading extracellular matrix proteins, is an important field of cancer research. We report here a novel strategy for assembling MMP inhibitors on the basis of oligopeptide ligands by exploring the pattern known as the zinc finger motif. Advanced molecular modeling tools were used to characterize the structural binding motifs of experimentally tested MMP inhibitors, as well as those of newly proposed peptidomimetics, in their zinc-containing active sites. The results of simulations based on the quantum mechanics/molecular mechanics (QM/MM) approach and Car–Parrinello molecular dynamics with QM/MM potentials demonstrate that, upon binding of Regasepin1, a known MMP-9 inhibitor, the Zn2+(His3) structural element is rearranged to the Zn2+(Cys2His2) zinc finger motif, in which two Cys residues are borrowed from the...  Read more

Catalytic Mechanism of Retroviral Integrase for the Strand Transfer Reaction Explored by QM/MM Calculations

Journal of Chemical Theory and Computation
Integrase (IN) is one of the three fundamental enzymes for the HIV life cycle. It irreversibly inserts the viral DNA into the host DNA, infecting the host cells. Although there are 37 compounds currently used in the HIV-1 antiretroviral therapy, only three have IN as a target. Lack of structural and mechanistic information on IN greatly contributes to such a small number. Prototype Foamy Virus (PFV) IN has an enzymatic activity remarkably similar to HIV IN and is considered a model system to study the catalytic mechanism of HIV IN. Recently, the crystal structure of the PFV intasome became available, which allowed us to perform accurate high-level quantum mechanics/molecular mechanics (QM/MM) calculations to determine the strand transfer reaction mechanism followed by IN. We describe here, for the first time with atomic detail, the integration of a viral genome into the DNA of a host cell. We found that the strand transfer reaction mechanism has three distinct steps: deprotonation and...  Read more

Large-Scale B3LYP Simulations of Ibuprofen Adsorbed in MCM-41 Mesoporous Silica as Drug Delivery System

The Journal of Physical Chemistry C
The atomistic details of the interaction between ibuprofen (one of the most common nonsteroidal anti-inflammatory drugs) and a realistic model of MCM-41 (one of the most studied mesoporous silica materials for drug delivery) were elucidated by quantum mechanical modeling inclusive of London forces. Calculations are based on periodic density functional theory adopting all-electron Gaussian-type basis functions of polarized double-ζ quality and the B3LYP hybrid functional. By docking the drug on different sites of the MCM-41 pore walls, we have sampled different local features of the potential energy surface of the drug–silica system, both for low and high loadings (one and seven drug molecules per unit cell, respectively). For all cases, ibuprofen adsorption in MCM-41 is exothermic (average ΔH = −99 kJ·mol–1) and exergonic (average ΔG = −33 kJ·mol–1), exclusively when London interactions are taken into account due to their dominant...  Read more