Journal of Computational Chemistry

doi: 10.1002/jcc.25935pmid: N/A

doi: 10.1002/jcc.25936pmid: N/A

Pakdel, Majid; Raissi, Heidar; Hosseini, Seyede T.

doi: 10.1002/jcc.26192pmid: 32190916

Therapeutic efficiency of amphiphilic methotrexate–camptothecin (MTX‐CPT) prodrug compared to free drug mixture (MTX/CPT) has been investigated using all‐atom molecular dynamics simulation and first principles density functional theory calculations. This comparison revealed that MTX–CPT prodrug tends to form spherical self‐assembled nanoparticle (NP), while free MTX/CPT mixture forms rod‐shape NP. These observations are attributed to a structural defect in the MTX–CPT prodrug and solvation free energies of MTX, CPT and MTX‐CPT molecules. The results provided evidence that noncovalent interactions (NCIs) among the pharmaceutical drugs play a very important role in anticancer agents aggregation process, leading to enhanced stability of the self‐assembled NPs. It is found that the stability of MTX–CPT self‐assembled NP is greater than the MTX/CPT NP due to the synergistic effect of hydrogen bonding between monomers and solvent (water). Moreover, the noncatalyzed as well as catalyzed hydrolysis reactions of MTX–CPT prodrug are theoretically studied at the PCM(water)//M06‐2X/6−31G(d,p) computational level to shed additional light on the role of acidic condition in tumor tissues. We found that the ester hydrolysis in mild acidic solutions is a concerted reaction. In an agreement between theory and experiment, we also confirmed that the activation energies of the catalyzed‐hydrolysis steps are much lower than the activation energies of the corresponding steps in the noncatalyzed reaction. Thus, the MTX–CPT prodrug reveals very promising properties as a pH‐controlled drug delivery system.

Anjali, Bai A.; Suresh, Cherumuttathu H.

doi: 10.1002/jcc.26193pmid: 32289191

Substituent effect for a series of 5‐phenyl tris(8‐hydroxyquinolinato) M(III) complexes (Mq3) of aluminum, gallium, and indium are investigated using density functional theory (DFT) for the ground state properties and the time‐dependent version of DFT (TDDFT) for their absorption and emission properties. A comparison between the ground state energy of mer and fac isomers of all the complexes revealed that the mer configuration is always more stable than fac. The substituent effect is significantly reflected at the fluorescence maximum (λF) values whereas the effect is moderate at the absorption maximum (λabs) values. The molecular electrostatic potential (MESP) at the metal center (VM) and the most electron rich region indicated by MESP minimum (Vmin), located at the oxygen of phenoxide ring exhibit excellent correlations with the λF and Stokes shift (λF−λabs) values. The study suggests the use of Stokes shift as an experimental quantity to measure the excited state substituent effect while the Vmin or VM emerge as theoretical quantities to measure the same.

Šebesta, Filip; Šebera, Jakub; Sychrovský, Vladimír; Tanaka, Yoshiyuki; Burda, Jaroslav V.

doi: 10.1002/jcc.26194pmid: 32208552

The formation of the Hg–N3(T) bond between the 1‐methylthymine (T) molecule and the hydrated Hg2+ cation was explored with the combined quantum mechanics/molecular mechanics (QM/MM) method including Free Energy Perturbation corrections. The thermodynamic properties were determined in the whole pH range, when these systems were explicitly investigated and considered as the QM part: (1) T + [Hg(H2O)6]2+, (2) T + [Hg(H2O)5(OH)]+, (3) T + Hg(H2O)4(OH)2, and (4) N3‐deprotonated T + Hg(H2O)4(OH)2. The MM part contained only solvent molecules and counterions. As a result, the dependence of Gibbs‐Alberty reaction free energy on pH was obtained along the reaction coordinate. We found that an endoergic reaction in acidic condition up to pH < 4–5 becomes exoergic for a higher pH corresponding to neutral and basic solutions. The migration of the Hg2+ cation between N3 and O4/2 positions in dependence on pH is discussed as well. For the verification, DFT calculations of stationary points were performed confirming the qualitative trends of QM/MM MD simulations and NMR parameters were determined for them.

Alaidi, Osama; Aboul‐ela, Fareed

doi: 10.1002/jcc.26195pmid: 32220073

The realization that noncoding RNA is implicated in numerous cellular processes, makes it imperative to understand and predict RNA‐folding. RNA secondary structure prediction is more tractable than tertiary structure or protein structure. Yet insights into RNA structure–function relationships are complicated by coupling between RNA‐folding and ligand‐binding. Here, perturbations to equilibrium secondary structure conformational distributions for two riboswitches are calculated in the presence of bound cognate ligands. This work incorporates a key factor coupling ligand binding to RNA conformation but not considered in most previous calculations: the differential affinity of the ligand for a range of RNA‐folding intermediates. Significant shifts in the free energy landscape (FEL) due to the ligand occur for transcripts of lengths corresponding to the “decision window,” following transcription of the so‐called anti‐terminator helix. The results suggest how ligand perturbation can stabilize the formation of an intermediate conformation, readily facilitating terminator hairpin formation in the full‐length riboswitch.

Inamori, Mayu; Yoshikawa, Takeshi; Ikabata, Yasuhiro; Nishimura, Yoshifumi; Nakai, Hiromi

doi: 10.1002/jcc.26197pmid: 32220108

A spin‐flip time‐dependent density functional tight‐binding (SF‐TDDFTB) method is developed that describes target states as spin‐flipping excitation from a high‐spin reference state obtained by the spin‐restricted open shell treatment. Furthermore, the SF‐TDDFTB formulation is extended to long‐range correction (LC), denoted as SF‐TDLCDFTB. The LC technique corrects the overdelocalization of electron density in systems such as charge‐transfer systems, which is typically found in conventional DFTB calculations as well as density functional theory calculations using pure functionals. The numerical assessment of the SF‐TDDFTB method shows smooth potential curves for the bond dissociation of hydrogen fluoride and the double‐bond rotation of ethylene and the double‐cone shape of H3 as the simplest degenerate systems. In addition, numerical assessments of SF‐TDDFTB and SF‐TDLCDFTB for 39 S0/S1 minimum energy conical intersection (MECI) structures are performed. The SF‐TDDFTB and SF‐TDLCDFTB methods drastically reduce the computational cost with accuracy for MECI structures compared with SF‐TDDFT.

Ootani, Yusuke; Satoh, Aya; Harabuchi, Yu; Taketsugu, Tetsuya

doi: 10.1002/jcc.26199pmid: 32239685

The semiclassical tunneling method is applied to evaluate the tunneling splitting of tropolone due to the intramolecular proton transfer in the electronic excited state, first time, in a framework of the trajectory on‐the‐fly molecular dynamics (TOF‐MD) approach. To prevent unphysical zero‐point vibrational energy transfer among the normal modes of vibration, quantum zero‐point vibrational energies are assigned only to the vibrational modes related to intramolecular proton transfer, whereas the remaining modes are treated as bath modes. Practical ways to determine the tunnel‐initiating points and tunneling path are introduced. It is shown that the tunneling splitting decreases as the bath‐mode energy increases. The experimental tunneling splitting value is well reproduced by the present TOF‐MD approach based on the Wentzel‐Kramers‐Brillouin (WKB) approximation.

Kasper, Joseph M.; Li, Xiaosong

doi: 10.1002/jcc.26196pmid: 32220083

While the natural transition orbital (NTO) method has allowed electronic excitations from time‐dependent Hartree‐Fock and density functional theory to be viewed in a traditional orbital picture, the extension to multicomponent molecular orbitals such as those used in relativistic two‐component methods or generalized Hartree‐Fock (GHF) or generalized Kohn‐Sham (GKS) is less straightforward due to mixing of spin‐components and the inherent inclusion of spin‐flip transitions in time‐dependent GHF/GKS. An extension of single‐component NTOs to the two‐component framework is presented, in addition to a brief discussion of the practical aspects of visualizing two‐component complex orbitals. Unlike the single‐component analog, the method explicitly describes the spin and frequently obtains solutions with several significant orbital pairs. The method is presented using calculations on a mercury atom and a CrO2Cl2 complex.

Larsson, Per; Kneiszl, Rosita C.; Marklund, Erik G.

doi: 10.1002/jcc.26198pmid: 32282082

The absolute performance of any all‐atom molecular dynamics simulation is typically limited by the length of the individual timesteps taken when integrating the equations of motion. In the GROMACS simulation software, it has for a long time been possible to use so‐called virtual sites to increase the length of the timestep, resulting in a large gain of simulation efficiency. Up until now, support for this approach has in practice been limited to the standard 20 amino acids however, shrinking the applicability domain of virtual sites. MkVsites is a set of python tools which provides a convenient way to obtain all parameters necessary to use virtual sites for virtually any molecules in a simulation. Required as input to MkVsites is the molecular topology of the molecule(s) in question, along with a specification of where to find the parent force field. As such, MkVsites can be a very valuable tool suite for anyone who is routinely using GROMACS for the simulation of molecular systems.