Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations

The Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) and the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) methods calculate binding free energies for macromolecules by combining molecular mechanics calculations and continuum solvation models. To systematically evaluate the performance of these methods, we report here an extensive study of 59 ligands interacting with six different proteins. First, we explored the effects of the length of the molecular dynamics (MD) simulation, ranging from 400 to 4800 ps, and the solute dielectric constant (1, 2, or 4) on the binding free energies predicted by MM/PBSA. The following three important conclusions could be observed: (1) MD simulation length has an obvious impact on the predictions, and longer MD simulation is not always necessary to achieve better predictions. (2) The predictions are quite sensitive to the solute dielectric constant, and this parameter should be carefully determined according to the characteristics of the protein/ligand binding interface. (3) Conformational entropy often show large fluctuations in MD trajectories, and a large number of snapshots are necessary to achieve stable predictions. Next, we evaluated the accuracy of the binding free energies calculated by three Generalized Born (GB) models. We found that the GB model developed by Onufriev and Case was the most successful model in ranking the binding affinities of the studied inhibitors. Finally, we evaluated the performance of MM/GBSA and MM/PBSA in predicting binding free energies. Our results showed that MM/PBSA performed better in calculating absolute, but not necessarily relative, binding free energies than MM/GBSA. Considering its computational efficiency, MM/GBSA can serve as a powerful tool in drug design, where correct ranking of inhibitors is often emphasized.     

Like-charge guanidinium pairing from molecular dynamics and ab initio calculations

Pairing of guanidinium moieties in water is explored by molecular dynamics simulations of short arginine-rich peptides and ab initio calculations of a pair of guanidinium ions in water clusters of increasing size. Molecular dynamics simulations show that, in an aqueous environment, the diarginine guanidinium like-charged ion pairing is sterically hindered, whereas in the Arg-Ala-Arg tripeptide, this pairing is significant. This result is supported by the survey of protein structure databases, where it is found that stacked arginine pairs in dipeptide fragments exist solely as being imposed by the protein structure. In contrast, when two arginines are separated by a single amino acid, their guanidinium groups can freely approach each other and they frequently form stacked pairs. Molecular dynamics simulations results are also supported by ab initio calculations, which show stabilization of stacked guanidinium pairs in sufficiently large water clusters.     

Controlling the shape and flexibility of arylamides: a combined ab initio, ab initio molecular dynamics, and classical molecular dynamics study

Using quantum chemistry plus ab initio molecular dynamics and classical molecular dynamics methods, we address the relationship between molecular conformation and the biomedical function of arylamide polymers. Specifically, we have developed new torsional parameters for a class of these polymers and applied them in a study of the interaction between a representative arylamide and one of its biomedical targets, the anticoagulant drug heparin. Our main finding is that the torsional barrier of a C(aromatic)-C(carbonyl) bond increases significantly upon addition of an o-OCH2CH2NH3+ substituent on the benzene ring. Our molecular dynamics studies that are based on the original general AMBER force field (GAFF) and GAFF modified to include our newly developed torsional parameters show that the binding mechanism between the arylamide and heparin is very sensitive to the choice of torsional potentials. Ab initio molecular dynamics simulation of the arylamide independently confirms the degree of flexibility we obtain by classical molecular dynamics when newly developed torsional potentials are used.     

Investigation of possible structures of silicon nanotubes via density-functional tight-binding molecular dynamics simulations and ab initio calculations

We show, computationally, that single-walled silicon nanotubes (SiNTs) can adopt a number of distorted tubular structures, representing respective local energy minima, depending on the theory used and the initial models adopted. In particular, "gearlike" structures containing alternating sp(3)-like and sp(2)-like silicon local configurations have been found to be the dominant structural form for SiNTs via density-functional tight-binding molecular dynamics simulations (followed by geometrical optimization using Hartree-Fock or density function theory) at moderate temperatures (below 100 K). The gearlike structures of SiNTs deviate considerably from, and are energetically more stable than, the smooth-walled tubes (the silicon analogues of single-walled carbon nanotubes). They are, however, energetically less favorable than the "string-bean-like" SiNT structures previously derived from semiempirical molecular orbital calculations. The energetics and the structures of gearlike SiNTs are shown to depend primarily on the diameter of the tube, irrespective of the type (zigzag, armchair, or chiral). In contrast, the energy gap is very sensitive to both the diameter and the type of the nanotube.     

Insights into mechanistic photodissociation of acetyl chloride by ab initio calculations and molecular dynamics simulations

The potential energy surfaces of dissociation and elimination reactions for CH(3)COCl in the ground (S0) and first excited singlet (S1) states have been mapped with the different ab inito calculations. Mechanistic photodissociation of CH(3)COCl has been characterized through the intrinsic reaction coordinate and ab initio molecular dynamics calculations. The alpha-C-C bond cleavage along the S1 pathway leads to the fragments of COCl((2)A' ') and CH(3) ((2)A') in an excited electronic state and a high barrier exists on the pathway. This channel is inaccessible in energy upon photoexcitation of the CH(3)COCl molecules at 236 nm. The S1 alpha-C-Cl bond cleavage yields the Cl((2)P) and CH(3)CO(X(2)A') fragments in the ground state and there is very small or no barrier on the pathway. The S1 alpha-C-Cl bond cleavage proceeds in a time scale of picosecond in the gas phase, followed by CH(3)CO decomposition to CH(3) and CO. The barrier to the C-Cl bond cleavage on the S1 surface is significantly increased by effects of the argon matrix. The S1 alpha-C-Cl bond cleavage in the argon matrix becomes inaccessible in energy upon photoexcitation of CH(3)COCl at 266 nm. In this case, the excited CH(3)COCl(S1) molecules cannot undergo the C-Cl bond cleavage in a short period. The internal conversion from S1 to S0 becomes the dominant process for the CH(3)COCl(S1) molecules in the condensed phase. As a result, the direct HCl elimination in the ground state becomes the exclusive channel upon 266 nm photodissociation of CH(3)COCl in the argon matrix at 11 K.     

Gold(I) in liquid ammonia: ab initio QM/MM molecular dynamics simulation

Structure and dynamics investigations of Au(I) ion in liquid ammonia have been performed by means of a molecular dynamics simulation based on ab initio quantum mechanical/molecular mechanical forces, where the first solvation shell was treated by quantum mechanics at Hartree-Fock level. The outer region of the system was described using a newly constructed classical three-body corrected potential. A rigid structure of the first solvation shell was observed with an average Au-N distance of 2.15 A and a coordination number of 2.0.     

Insights into photodissociation dynamics of propionyl chloride from ab initio calculations and molecular dynamics simulations

The potential energy surfaces of isomerization, dissociation, and elimination reactions for CH3CH2COCl in the S0 and S1 states have been mapped with the different ab initio calculations. Mechanistic photodissociation of CH3CH2COCl at 266 nm has been characterized through the computed potential energy surfaces, the optimized surface crossing structure, intrinsic reaction coordinate, and ab initio molecular dynamics calculations. Photoexcitation at 266 nm leads to the CH3CH2COCl molecules in the S1 state. From this state, the C-Cl bond cleavage proceeds in a time scale of picosecond in the gas phase. The barrier to the C-Cl bond cleavage on the S1 surface is significantly increased by effects of the matrix and the internal conversion to the ground state prevails in the condensed phase. The HCl eliminations as a result of internal conversion to the ground state become the dominant channel upon photodissociation of CH3CH2COCl in the argon matrix at 10 K.     

Structure and dynamics of hydrated NH(4) (+): an ab initio QM/MM molecular dynamics simulation

A combined ab initio quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulation has been performed to investigate solvation structure and dynamics of NH(4) (+) in water. The most interesting region, the sphere includes an ammonium ion and its first hydration shell, was treated at the Hartree-Fock level using DZV basis set, while the rest of the system was described by classical pair potentials. On the basis of detailed QM/MM simulation results, the solvation structure of NH(4) (+) is rather flexible, in which many water molecules are cooperatively involved in the solvation shell of the ion. Of particular interest, the QM/MM results show fast translation and rotation of NH(4) (+) in water. This phenomenon has resulted from multiple coordination, which drives the NH(4) (+) to translate and rotate quite freely within its surrounding water molecules. In addition, a "structure-breaking" behavior of the NH(4) (+) is well reflected by the detailed analysis on the water exchange process and the mean residence times of water molecules surrounding the ion.     

Characterization of structure and dynamics of an aqueous scandium(iii) ion by an extended ab initio QM/MM molecular dynamics simulation

Hydration structure and dynamics of an aqueous Sc(iii) solution were characterized by means of an extended ab initio quantum mechanical/molecular dynamical (QM/MM) molecular dynamics simulation at Hartree-Fock level. A monocapped trigonal prismatic structure composed of seven water molecules surrounding scandium(iii) ion was proposed by the QM/MM simulation including the quantum mechanical effects for the first and second hydration shells. The mean Sc(iii)-O bond length of 2.14 ? was identified for six prism water molecules with one capping water located at around 2.26 ?, reproducing well the X-ray diffraction data. The Sc(iii)-O stretching frequency of 432 cm(-1) corresponding to a force constant of 130 N m(-1), evaluated from the enlarged QM/MM simulation, is in good agreement with the experimentally determined value of 430 cm(-1) (128 N m(-1)). Various water exchange processes in the second hydration shell of the hydrated Sc(iii) ion predict a mean ligand residence time of 7.3 ps.     

Structure of isolated tryptophyl-glycine dipeptide and tryptophyl-glycyl-glycine tripeptide: ab initio SCC-DFTB-D molecular dynamics simulations and high-level correlated ab initio quantum chemical calculations

The tryptophyl-glycine (Trp-Gly) and tryptophyl-glycyl-glycine (Trp-Gly-Gly) peptides have been studied by means of molecular dynamic simulations combined with high-level correlated ab initio quantum chemical and statistical thermodynamic calculations. The lowest energy conformers were localized in the free energy surface. The structures of the different Trp-Gly and Trp-Gly-Gly conformers coexisting in the gas phase have been for the first time reported and their scaled theoretical IR spectra unambiguously assigned and compared with previous gas-phase experimental results. Common geometrical features have been systematically observed for the sequence Trp, Trp-Gly, and Trp-Gly-Gly. In addition, the peptide backbone of Trp-Gly-Gly has been compared with that of the previously studied Phe-Gly-Gly (Reha, D. et. al. Chem. Eur. J. 2005, 11, 6803). From the observed systematic structural behavior between these peptide analogues, it is expected that the gas-phase conformers of other similar aromatic small peptides would present equivalent geometries. The DFT methodology failed to describe the potential energy surface of the studied peptides since the London dispersion energy (not covered in DFT) plays a significant role in the stabilization of most stable conformers.     

Organolithium complex as a gas sensing material for oxides from ab initio calculations and molecular dynamics simulations

Gas sensing study of C₂H₄Li complex toward oxides viz. CO, CO₂, NO, NO₂, SO, and SO₂ gas molecules has been carried out using ab initio method. Different possible configurations of gas molecule adsorption on C₂H₄Li complex are considered. The structural parameters of most stable configuration of gas molecule adsorbed complexes are thoroughly analysed. Electronic properties are studied using total density of states (DOS) plot. Charge transferred between the gas molecule and the substrate is studied using NBO charge analysis. Gas sensing of all the six gas molecules is possible at ambient conditions. Atom centred density matrix propagation (ADMP) molecular dynamics simulations confirmed that all the gas molecules remain adsorbed on C₂H₄Li complex at room temperature during the simulation. This study suggests that the C₂H₄Li complex acts as a novel gas sensing material for CO, CO₂, NO, NO₂, SO, and SO₂ gas molecules at ambient conditions, below room temperature as well as at high pressure.     

Increasing the time step with mass scaling in Born‐Oppenheimer ab initio QM/MM molecular dynamics simulations

Born‐Oppenheimer ab initio QM/MM molecular dynamics simulation with umbrella sampling is a state‐of‐the‐art approach to calculate free energy profiles of chemical reactions in complex systems. To further improve its computational efficiency, a mass‐scaling method with the increased time step in MD simulations has been explored and tested. It is found that by increasing the hydrogen mass to 10 amu, a time step of 3 fs can be employed in ab initio QM/MM MD simulations. In all our three test cases, including two solution reactions and one enzyme reaction, the resulted reaction free energy profiles with 3 fs time step and mass scaling are found to be in excellent agreement with the corresponding simulation results using 1 fs time step and the normal mass. These results indicate that for Born‐Oppenheimer ab initio QM/MM molecular dynamics simulations with umbrella sampling, the mass‐scaling method can significantly reduce its computational cost while has little effect on the calculated free energy profiles. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009     

A combination of molecular dynamics and docking calculations to explore the binding mode of ADS-J1, a polyanionic compound endowed with anti-HIV-1 activity

The HIV-1 entry process is an important target for the design of new pharmaceuticals for the multidrug therapy of AIDS. A lot of polyanionic compounds, such as polysulfonated and polysulfated, are reported in the literature for their ability to block early stages of HIV-1 replication. Several studies have been performed to elucidate the mechanism of the anti-HIV-1 activity of sulfated polysaccharides and polyanions in general, including binding to cell surface CD4 and interfering with the gp120-coreceptor interaction. Here, we show molecular modeling investigations on ADS-J1, a polyanionic compound with anti-HIV activity that is able to interfere with gp120-coreceptor interactions. Agreeing with experimental data, computer simulations suggested that the V3 loop of gp120 was the preferential binding site for ADS-J1 onto HIV-1. Moreover, mutations induced by the inhibitor significantly changed the stereoelectronic properties of the gp120 surface, justifying a marked drop in the affinity of ADS-J1 toward an ADS-J1-resistant HIV-1 strain.     

The Jahn-Teller effect of the TiIII ion in aqueous solution: extended ab initio QM/MM molecular dynamics simulations.

Combined ab initio quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations, including only the first and the first and second hydration shells in the QM region, were performed for TiIII in aqueous solution. The hydration structure of TiIII is discussed in terms of radial distribution functions, coordination-number distributions and several angle distributions. Dynamical properties, such as librational and vibrational motions and TiIII-O vibrations, were evaluated. A fast dynamical Jahn-Teller effect of TiIII(aq) was observed in the QM/MM simulations, in particular when the second hydration shell was included into the QM region. The results justify the computational effort required for the inclusion of the second hydration shell into the QM region and show the importance of this effort for obtaining accurate hydration-shell geometries, dynamical properties, and details of the Jahn-Teller effect.     

IMiCMO: a new integrated ab initio multicenter molecular orbitals method for molecular dynamics calculations in solvent cluster systems

A new computational scheme integrating ab initio multicenter molecular orbitals for determining forces of individual atoms in large cluster systems is presented. This method can be used to treat systems of many molecules, such as solvents by quantum mechanics. The geometry parameters obtained for three models of water clusters by the present method are compared with those obtained by the full ab initio MO method. The results agree very well. The scheme proposed in this article also intended for use in modeling cluster systems using parallel algorithms. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1107–1112, 2001     

Spectroscopic properties in the liquid phase: combining high-level ab initio calculations and classical molecular dynamics.

We present an integrated computational tool, rooted in density functional theory, the polarizable continuum model, and classical molecular dynamics employing spherical boundary conditions, to study the spectroscopic observables of molecules in solution. As a test case, a modified OPLS-AA force field has been developed and used to compute the UV and NMR spectra of acetone in aqueous solution. The results show that provided the classical force fields are carefully reparameterized and validated, the proposed approach is robust and effective, and can also be used by nonspecialists to provide a general and powerful complement to experimental techniques.