Journal of Computational Chemistry

doi: 10.1002/jcc.26911pmid: N/A

Cao, Siqin; Kalin, Michael L.; Huang, Xuhui

doi: 10.1002/jcc.27088pmid: 36856731

Integral equation theory (IET) provides an effective solvation model for chemical and biological systems that balances computational efficiency and accuracy. We present a new software package, the expanded package for IET‐based solvation (EPISOL), that performs 3D‐reference interaction site model (3D‐RISM) calculations to obtain the solvation structure and free energies of solute molecules in different solvents. In EPISOL, we have implemented 22 different closures, multiple free energy functionals, and new variations of 3D‐RISM theory, including the recent hydrophobicity‐induced density inhomogeneity (HI) theory for hydrophobic solutes and ion‐dipole correction (IDC) theory for negatively charged solutes. To speed up the convergence and enhance the stability of the self‐consistent iterations, we have introduced several numerical schemes in EPISOL, including a newly developed dynamic mixing approach. We show that these schemes have significantly reduced the failure rate of 3D‐RISM calculations compared to AMBER‐RISM software. EPISOL consists of both a user‐friendly graphic interface and a kernel library that allows users to call its routines and adapt them to other programs. EPISOL is compatible with the force‐field and coordinate files from both AMBER and GROMACS simulation packages. Moreover, EPISOL is equipped with an internal memory control to efficiently manage the use of physical memory, making it suitable for performing calculations on large biomolecules. We demonstrate that EPISOL can efficiently and accurately calculate solvation density distributions around various solute molecules (including a protein chaperone consisting of 120,715 atoms) and obtain solvent free energy for a wide range of organic compounds. We expect that EPISOL can be widely applied as a solvation model for chemical and biological systems. EPISOL is available at https://github.com/EPISOLrelease/EPISOL.

Haritha, Mambatta; Suresh, Cherumuttathu H.

doi: 10.1002/jcc.27107pmid: 36971443

The OCNH unit is one of the most frequently encountered structural motifs in rings in drugs which serves dual role as the proton donor through NH bond and proton acceptor through the CO bond. Here, we predicted the HB strength (Eint) of OCNH motif with H2O for commonly observed 37 rings in drugs with DFT method M06L/6‐311++G(d,p). The HB strength is rationalized in terms of molecular electrostatic potential (MESP) topology parameters ΔVn(NH) and ΔVn(CO) which describe the relative electron deficient/rich nature of NH and CO, respectively, with respect to the reference formamide. The Eint of formamide is −10.0 kcal/mol whereas the Eint of ring systems is in the range −8.6 to −12.7 kcal/mol—a minor increase/decrease compared to the formamide. The variations in Eint are addressed using the MESP parameters ΔVn(NH) and ΔVn(CO) and proposed the hypothesis that a positive ΔVn(NH) enhances NH…Ow interaction while a negative ΔVn(CO) enhances the CO…Hw interaction. The hypothesis is proved by expressing Eint jointly as ΔVn(NH) and ΔVn(CO) and also verified for twenty FDA approved drugs. The predicted Eint for the drugs using ΔVn(NH) and ΔVn(CO) agreed well with the calculated Eint. The study confirms that even delicate variations in the electronic feature of a molecule can be quantified in terms of MESP parameters and they provide a priori prediction of the HB strength. The MESP topology analysis is recommended to understand the tunability of HB strength in drug motifs.

Panthi, Bhavana; Dutta, Saheb; Chandra, Amalendu

doi: 10.1002/jcc.27108pmid: 37000187

The spike protein of SARS‐CoV‐2 exists in two major conformational states, namely the ‘open’ and ‘closed’ states which are also known as the ‘up’ and ‘down’ states, respectively. In its open state, the receptor binding domain (RBD) of the protein is exposed for binding with ACE2, whereas the spike RBD is inaccessible to ACE2 in the closed state of the protein. In the current work, we have performed all‐atom microsecond simulations of the full‐length trimeric spike protein solvated in explicit aqueous medium with an average system size of ~0.7 million atoms to understand the molecular nature of intra‐ and inter‐chain interactions, water‐bridged interactions between different residues that contribute to the stability of the open and closed states of the protein, and also the free energy landscape for transition between the open and closed states of the protein. We have also examined the changes of such interactions that are associated with switching from one state to the other through both unbiased and biased simulations at all‐atom level with total run length of 4 μs. Interestingly, after about 0.8 μs of unbiased molecular dynamics run of the spike system in the open state, we observed a gradual transition of the monomeric chain (B) from open to its partially closed or down state. Initially the residues at the interface of chain B RBD in the open state spike protein were at non‐hydrogen‐bonding distances from the residues of chain C RBD. However, the two RBDs gradually came closer and finally the residue S459 of the RBD of chain B made a hydrogen bond with F374 of chain C in the last 200 ns of the simulation along with formation of a few more hydrogen bonds involving other residues. Since no transition from closed to the open state of the protein is observed in the present 1 μs unbiased simulation of the closed state protein, the current study seems to suggest that the closed conformational state is preferred for the spike protein of SARS‐CoV‐2 in aqueous medium. Furthermore, calculations of the free energy surface of the conformational transition from open (up) to the closed (down) state using a biased simulation method reveal a free energy barrier of ~3.20 kcal/mol for the transition of RBD from open to the closed state, whereas the barrier for the reverse process is found to be significantly higher.

Pagola, G. I.; Provasi, P. F.; Ferraro, M. B.; Lazzeretti, P.

doi: 10.1002/jcc.27109pmid: 37026434

The diagonal components and the trace of two tensors which account for chiroptical response of the leucoindigo molecule C16H12N2O2 that is, static anapole magnetizability, and dynamic electric dipole‐magnetic dipole polarisability depending on the frequency of impinging light, are a function of the ϕ dihedral angle of torsion about the central CC bond, assumed to lie in the y direction of the coordinate system. They vanish for symmetry reasons at ϕ=0∘ and ϕ=180∘, corresponding respectively to C2v and C2h point group symmetries, that is, cis and trans conformers characterized by the presence of molecular symmetry planes. Nonetheless, diagonal components and average value of static anapole polarizability and optical rotation tensors vanish at ϕ=90∘, where leucondigo is unquestionably chiral from the geometrical viewpoint. Vanishing values of the average chiroptical properties have been observed also in the proximity of other ϕ angles. Attempts have been made to explain the occurrence of accidental zeros of chiroptical properties in terms of transition frequencies and scalar products appearing in the numerator of their quantum mechanical definitions. Within the electric dipole approximation, the presence of anomalous vanishing values of tensor components of anapole magnetizability and electric‐magnetic dipole polarizability is ascribed to physical achirality, arising from the lack of either toroidal or spiral electron flow along the x, y and z directions.

Valdés, Álvaro; Cabrera‐Ramírez, Adriana; Prosmiti, Rita

doi: 10.1002/jcc.27110pmid: 37013410

We report new results on the translational‐rotational (T‐R) states of the CO2 molecule inside the sI clathrate‐hydrate cages. We adopted the multiconfiguration time‐dependent Hartree methodology to solve the nuclear molecular Hamiltonian, and to address issues on the T‐R couplings. Motivated by experimental X‐ray observations on the CO2 orientation in the D and T sI cages, we aim to evaluate the effect of the CO2–water interaction on quantum dynamics. Thus, we first compared semiempirical and ab initio‐based pair interaction model potentials against first‐principles DFT‐D calculations for ascertaining the importance of nonadditive many‐body effects on such guest–host interactions. Our results reveal that the rotational and translational excited states quantum dynamics is remarkably different, with the pattern and density of states clearly affected by the underlying potential model. By analyzing the corresponding the probability density distributions of the calculated T‐R eigenstates on both semiempirical and ab initio pair CO2–water nanocage potentials, we have extracted information on the altered CO2 guest local structure, and we discussed it in connection with experimental data on the orientation of the CO2 molecule in the D and T sI clathrate cages available from neutron diffraction and 13C solid‐state NMR studies, as well as in comparison with previous molecular dynamics simulations. Our calculations provide a very sensitive test of the potential quality by predicting the low‐lying T‐R states and corresponding transitions for the encapsulated CO2 molecule. As such spectroscopic observables have not been measured so far, our results could trigger further detailed experimental and theoretical investigations leading to a quantitative description of the present guest–host interactions.