Periodic Boundary Conditions in QM/MM Calculations: Implementation and Tests

Journal of Chemical Theory and Computation
Quantum mechanics/molecular mechanics (QM/MM) simulations of reactions in solutions and in solvated enzymes can be performed using the QM/MM-Ewald approach with periodic boundary conditions (PBC) or a nonperiodic treatment with a finite solvent shell (droplet model). To avoid the changes in QM codes that are required in standard QM/MM-Ewald implementations, we present a general method (Gen-Ew) for periodic QM/MM calculations that can be used with any QM method in the QM/MM framework. The Gen-Ew approach approximates the QM/MM-Ewald method by representing the PBC potential by virtual charges on a sphere and the QM density by electrostatic potential (ESP) charges. Test calculations show that the deviations between Gen-Ew and QM/MM-Ewald results are generally small enough to justify the application of the Gen-Ew method in the absence of a suitable QM/MM-Ewald implementation. We compare the results from periodic QM/MM calculations (QM/MM-Ewald, Gen-Ew) to their nonperiodic counterparts...  Read more

Assessing the performance of the MM/PBSA and MM/GBSA methods. 6. Capability to predict protein–protein binding free energies and re-rank binding poses generated by protein–protein docking

Physical Chemistry Chemical Physics
Understanding protein–protein interactions (PPIs) is quite important to elucidate crucial biological processes and even design compounds that interfere with PPIs with pharmaceutical significance. Protein–protein docking can afford the atomic structural details of protein–protein complexes, but the accurate prediction of the three-dimensional structures for protein–protein systems is still notoriously difficult due in part to the lack of an ideal scoring function for protein–protein docking. Compared with most scoring functions used in protein–protein docking, the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) and Molecular Mechanics/Poisson Boltzmann Surface Area (MM/PBSA) methodologies are more theoretically rigorous, but their overall performance for the predictions of binding affinities and binding poses for protein–protein systems has not been systematically evaluated. In this study, we first evaluated the performance of MM/PBSA and MM/GBSA to predict...  Read more

Electrostatic Interaction-Induced Room-Temperature Phosphorescence in Pure Organic Molecules from QM/MM Calculations

The Journal of Physical Chemistry Letters
Room temperature phosphorescence (RTP) from pure organic material is rare due to the low phosphorescence quantum efficiency. That is why the recent discovery of crystallization induced RTP for several organic molecules aroused strong interests. Through a combined quantum and molecular mechanics CASPT2/AMBER scheme taking terephthalic acid (TPA) as example, we found that electrostatic interaction not only can induce an enhanced radiative decay T1 → S0 through the dipole-allowed S1 intermediate state, but also can hinder the nonradiative decay process upon crystallization. From gas phase to crystal, the nature of S1 state is converted to 1(π,π*) from 1(n,π*) character, enhancing transition dipole moment and serving as an efficient intermediate radiative pathway for T1 → S0 transition, and eventually leading to a boosted RTP. The intermolecular packing also blocks the nonradiative decay channel...  Read more

The influence of metal-ion binding on the structure and surface composition of Sonic Hedgehog: a combined classical and hybrid QM/MM MD study

Physical Chemistry Chemical Physics
In this work, the influence of the metal ions present in vertebrate Sonic Hedgehog was assessed by a series of molecular mechanics molecular dynamics simulations with differing ionic compositions. The obtained data suggest that Ca(II) binding has a very distinct influence on the composition of the protein surface surrounding the binding site by shaping several ionic interactions with negatively charged sidechains that otherwise would be pointing towards the solvent, repelling potential ligands. Furthermore, the Ca(II) ions play an important role in the stability of the loop regions where they are coordinated. In contrast, the removal of the Zn(II) ion results in no noticeable destabilization of its chemical surrounding, however, it is shown that the destabilizing effect of removed Ca(II) ions is amplified if Zn(II) is absent as well. Furthermore, a quantum mechanical/molecular mechanical (QM/MM) molecular...  Read more

QM/MM study of the mechanism of reduction of 3-hydroxy-3-methylglutaryl coenzyme A catalyzed by human HMG-CoA reductase

Catalysis Science & Technology
Detailing with atomistic resolution the reaction mechanism of human HMG-CoA reductase (HMG-CoA-R) might provide valuable insights for the development of new cholesterol-lowering drugs. In the pursuit of that goal we developed three molecular models of human HMG-CoA-R with different active site protonation states and employed molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) calculations to detail the first reduction step, the rate-limiting step, of HMG-CoA-R. Our results predict an active site with a neutral glutamate (Glu559) as the most catalytically competent structure. The favored reaction pathway suggests the formation of a mevaldyl-CoA intermediate protonated by a conserved active site lysine (Lys691), corroborating previous site-directed mutagenesis studies. The conserved active site glutamate and aspartate residues (Glu559 and Asp767), along with the ribose moiety of NADPH, form a hydrogen bond network crucial to the increase of the stabilizing effect...  Read more

Concentration Dependent Specific Rotations of Chiral Surfactants: Experimental and Computational Studies

The Journal of Physical Chemistry A
Recent experimental studies have shown unexpected chiroptical response from some chiral surfactant molecules, where the specific rotations changed significantly as a function of concentration. To establish a theoretical understanding of this experimentally observed phenomena, a novel methodology for studying chiral surfactants via combined molecular dynamics (MD) and quantum mechanical (QM) calculations is presented. MD simulations on the +10 000 atom surfactant systems have been performed using MD and QM/molecular mechanics (MM) approaches. QM calculations performed on MD snapshots coupled with extensive analysis on lauryl ester of phenylalanine (LEP) surfactant system indicate that the experimentally observed variation of specific rotation with concentration may be due to the conformational differences of the surfactant monomers in the aggregates. Though traditional MM simulations did not show significant differences in the conformer populations, QM/MM simulations using the forces...  Read more

Liquid-Phase Exfoliation of Graphite into Single- and Few-Layer Graphene with α-Functionalized Alkanes

The Journal of Physical Chemistry Letters
Graphene has unique physical and chemical properties, making it appealing for a number of applications in optoelectronics, sensing, photonics, composites, and smart coatings, just to cite a few. These require the development of production processes that are inexpensive and up-scalable. These criteria are met in liquid-phase exfoliation (LPE), a technique that can be enhanced when specific organic molecules are used. Here we report the exfoliation of graphite in N-methyl-2-pyrrolidinone, in the presence of heneicosane linear alkanes terminated with different head groups. These molecules act as stabilizing agents during exfoliation. The efficiency of the exfoliation in terms of the concentration of exfoliated single- and few-layer graphene flakes depends on the functional head group determining the strength of the molecular dimerization through dipole–dipole interactions. A thermodynamic analysis is carried out to interpret the impact of the termination group of the alkyl chain...  Read more

Quantum Chemical-Based Protocol for the Rational Design of Covalent Inhibitors

Journal of the American Chemical Society
We propose a structure-based protocol for the development of customized covalent inhibitors. Starting from a known inhibitor, in the first and second steps appropriate substituents of the warhead are selected on the basis of quantum mechanical (QM) computations and hybrid approaches combining QM with molecular mechanics (QM/MM). In the third step the recognition unit is optimized using docking approaches for the noncovalent complex. These predictions are finally verified by QM/MM or molecular dynamic simulations. The applicability of our approach is successfully demonstrated by the design of reversible covalent vinylsulfone-based inhibitors for rhodesain. The examples show that our approach is sufficiently accurate to identify compounds with the desired properties but also to exclude nonpromising ones.Read more

Molecular mechanics of the cooperative adsorption of a Pro-Hyp-Gly tripeptide on a hydroxylated rutile TiO2(110) surface mediated by calcium ions

Physical Chemistry Chemical Physics
The interaction of amino acids with inorganic materials at interfaces plays an important role in enhancing the biocompatibility of titanium-based alloys. The adsorption of a tripeptide, i.e. Pro-Hyp-Gly, on the hydroxylated rutile TiO2(110) surface was investigated by the MD simulations. The changes in free energy during the adsorption of both the tripeptide and calcium ions were calculated by using the PMF method in order to obtain the adsorption strength. The results suggested that the adsorption of the tripeptide on the TiO2 surface through the carboxyl groups in glycine residues can be more stable compared with other binding conformations. Special attention was focused on the cooperative adsorption of the tripeptide with the assistance of calcium ions. Calcium ions preferred to absorb at the tetradentate or monodentate sites on the negatively charged TiO2 surface. As a result of the strong...  Read more

A QM/MM Approach Using the AMOEBA Polarizable Embedding: From Ground State Energies to Electronic Excitations

Journal of Chemical Theory and Computation
A fully polarizable implementation of the hybrid quantum mechanics/molecular mechanics approach is presented, where the classical environment is described through the AMOEBA polarizable force field. A variational formalism, offering a self-consistent relaxation of both the MM induced dipoles and the QM electronic density, is used for ground state energies and extended to electronic excitations in the framework of time-dependent density functional theory combined with a state specific response of the classical part. An application to the calculation of the solvatochromism of the pyridinium N-phenolate betaine dye used to define the solvent ET(30) scale is presented. The results show that the QM/AMOEBA model not only properly describes specific and bulk effects in the ground state but it also correctly responds to the large change in the solute electronic charge distribution upon excitation.Read more

Unraveling the aggregation effect on amorphous phase AIE luminogens: a computational study

To achieve the efficient and precise regulation of aggregation-induced emission (AIE), unraveling the aggregation effects on amorphous AIE luminogens is of vital importance. Using a theoretical protocol combining molecular dynamics simulations and quantum mechanics/molecular mechanics calculations, we explored the relationship between molecular packing, optical spectra and fluorescence quantum efficiency of amorphous AIE luminogens hexaphenylsilole (HPS). We confirmed that the redshifted emission of amorphous aggregates as compared to crystalline HPS is caused by the lower packing density of amorphous HPS aggregates and the reduced restrictions on their intramolecular low-frequency vibrational motions. Strikingly, our calculations revealed the size independent fluorescence quantum efficiency of nanosized HPS aggregates and predicted the linear relationship between the fluorescence intensity and aggregate size. This is because the nanosized aggregates are dominated by embedded HPS...  Read more

Toward Mesoscale Properties of Self-Assembled Monolayers of SMM on Au(111): An Integrated Ad Hoc FF and DFT Study

The Journal of Physical Chemistry C
In nanotechnology, a preservation of the electronic and magnetic properties of an adsorbated molecular system and the control of its organization on a surface is mandatory for any technological application. Recently, in silico approaches demonstrated to be of fundamental support to experimental investigations in this hot and promising field. In this framework, an integrated MM (molecular mechanics) and DFT (density functional theory) approach for the modelization of single molecule magnets (SMMs) on surface has been developed and applied to study the adsorption of [Fe4(L)2(dpm)6] (Hdpm = dipivaloylmethane and H3L = 2-hydroxymethyl-2-phenylpropane-1,3-diol), Fe4Ph, on an unreconstructed surface of Au(111). The adsorption process and its effects on the geometrical parameters and the magnetic properties are presented. The proposed method shows to be reliable enough to pave the route toward the access to the mesoscopic...  Read more

Theoretical study of the hydrolysis mechanism of dihydrocoumarin catalyzed by serum paraoxonase 1 (PON1): different roles of Glu53 and His115 for catalysis

RSC Advances
Serum paraoxonase 1 (PON1) is a calcium-dependent enzyme that can catalyze the hydrolysis of multiple substrates, including lactones, thiolactones, carbonates, esters and phosphotriesters, as well as the formation of a variety of lactones. To better understand the lactonase mechanism of PON1, the hydrolysis of dihydrocoumarin, which is considered as a native substrate of PON1, has been investigated by using a combined quantum mechanics and molecular mechanics (QM/MM) approach. Two possible reaction pathways with either Glu53 or His115 acts as the general base have been considered. On the basis of our calculations, these two pathways correspond to the overall energy barriers of 12.5 and 9.0 kcal mol−1, respectively. During the catalytic reaction, if one of the two residues (Glu53 and His115) acts as the catalytic base, the other one forms strong hydrogen bonding interaction with the attacking hydroxide to facilitate the hydrolysis. However, mutation studies...  Read more

Extension of the Effective Fragment Potential Method to Macromolecules

The Journal of Physical Chemistry B
The effective fragment potential (EFP) approach, which can be described as a nonempirical polarizable force field, affords an accurate first-principles treatment of noncovalent interactions in extended systems. EFP can also describe the effect of the environment on the electronic properties (e.g., electronic excitation energies and ionization and electron-attachment energies) of a subsystem via the QM/EFP (quantum mechanics/EFP) polarizable embedding scheme. The original formulation of the method assumes that the system can be separated, without breaking covalent bonds, into closed-shell fragments, such as solvent and solute molecules. Here, we present an extension of the EFP method to macromolecules (mEFP). Several schemes for breaking a large molecule into small fragments described by EFP are presented and benchmarked. We focus on the electronic properties of molecules embedded into a protein environment and consider ionization, electron-attachment, and excitation energies...  Read more

Reaction mechanism of the dengue virus serine protease: a QM/MM study

Physical Chemistry Chemical Physics
The dengue virus (DENV) is the causative agent of the viral infection dengue fever. In spite of all the efforts made to prevent the spread of the disease, once it is contracted, there is no specific treatment for dengue and the WHO guidelines are limited to rest and symptomatic treatment. In its reproductive cycle, DENV utilizes the NS2B-NS3pro, a serine protease, to cleave the viral polyprotein into its constituents. This enzyme is essential for the virus lifecycle, and presents an attractive target for the development of specific dengue treatments. Here we used a hybrid Quantum Mechanics and Molecular Mechanics (QM/MM) Molecular Dynamics approach and Umbrella Sampling to study the first step (acylation) of the reaction catalyzed by NS2B-NS3pro, using the Pairwise Distance Directed Gaussian PM3 (PDDG/PM3) semi-empirical Hamiltonian for the QM subsystem, and Amber ff99SB for the MM subsystem. Our results indicate that the nucleophilic attack on the substrate by Ser135 occurs in a...  Read more

Influence of Polarization on Carbohydrate Hydration: A Comparative Study Using Additive and Polarizable Force Fields

The Journal of Physical Chemistry B
Carbohydrates are known to closely modulate their surrounding solvent structures and influence solvation dynamics. Spectroscopic investigations studying far-IR regions (below 1000 cm–1) have observed spectral shifts in the libration band (around 600 cm–1) of water in the presence of monosaccharides and polysaccharides. In this paper, we use molecular dynamics simulations to gain atomistic insight into carbohydrate–water interactions and to specifically highlight the differences between additive (nonpolarizable) and polarizable simulations. A total of six monosaccharide systems, α and β anomers of glucose, galactose, and mannose, were studied using additive and polarizable Chemistry at HARvard Macromolecular Mechanics (CHARMM) carbohydrate force fields. Solvents were modeled using three additive water models TIP3P, TIP4P, and TIP5P in additive simulations and polarizable water model SWM4 in polarizable simulations. The presence of carbohydrate has a...  Read more

Anthrax Edema Factor: An Ion-Adaptive Mechanism of Catalysis with Increased Transition-State Conformational Flexibility

The Journal of Physical Chemistry B
Edema Factor (EF) is one of three major toxins of anthrax. EF is an adenylyl cyclase that disrupts cell signaling by accelerating the conversion of ATP into cyclic-AMP. EF has a much higher catalytic rate than that of mammalian adenylyl cyclases (mACs). Crystal structures were obtained for mACs and EF, but the molecular basis for different catalytic activities remained poorly understood. In particular, the arrangement of the active site in EF is unclear in what concerns the number of ions present and the conformation of the substrate. Here, we use quantum mechanics–molecular mechanics simulations to estimate the free-energy profiles for the reaction catalyzed by EF and a mAC. We found that EF catalysis is possible, and faster than that of mACs, in both one and two Mg2+-ion-binding modes, providing adaptive plasticity to host-cell environments. In both enzymes, the reaction mechanisms are highly associative. However, mechanistic differences exist. In the mAC, the...  Read more

Computational Studies on Cinchona Alkaloid-Catalyzed Asymmetric Organic Reactions

Accounts of Chemical Research
Remarkable progress in the area of asymmetric organocatalysis has been achieved in the last decades. Cinchona alkaloids and their derivatives have emerged as powerful organocatalysts owing to their reactivities leading to high enantioselectivities. The widespread usage of cinchona alkaloids has been attributed to their nontoxicity, ease of use, stability, cost effectiveness, recyclability, and practical utilization in industry. The presence of tunable functional groups enables cinchona alkaloids to catalyze a broad range of reactions. Excellent experimental studies have extensively contributed to this field, and highly selective reactions were catalyzed by cinchona alkaloids and their derivatives. Computational modeling has helped elucidate the mechanistic aspects of cinchona alkaloid catalyzed reactions as well as the origins of the selectivity they induce. These studies have complemented experimental work for the design of more efficient catalysts. This Account presents recent...  Read more

Stereoselectivity in (Acyloxy)borane-Catalyzed Mukaiyama Aldol Reactions

The Journal of Organic Chemistry
The origin of diastereo- and enantioselectivity in a Lewis acid-catalyzed Mukaiyama aldol reaction is investigated using a combination of dispersion corrected DFT calculations and transition state force fields (TSFF) developed using the quantum guided molecular mechanics (Q2MM) method. The reaction proceeds via a closed transition structure involving a nontraditional hydrogen bond that is 3.3 kJ/mol lower in energy than the corresponding open transition structure. The correct prediction of the diastereoselectivity of a Mukaiyama aldol reaction catalyzed by the conformationally flexible Yamamoto chiral (acyloxy) borane (CAB) requires extensive conformational sampling at the transition structure, which is achieved using a Q2MM-derived TSFF, followed by DFT calculations of the low energy conformational clusters. Finally, a conceptual model for the rationalization of the observed diastereo- and enantioselectivity of the reaction using a closed transition state model is proposed.Read more

Mechanism of the Reaction of Human Manganese Superoxide Dismutase with Peroxynitrite: Nitration of Critical Tyrosine 34

Human Mn-containing superoxide dismutase (hMnSOD) is a mitochondrial enzyme that metabolizes superoxide radical (O2•–). O2•– reacts at diffusional rates with nitric oxide to yield a potent nitrating species, peroxynitrite anion (ONOO). MnSOD is nitrated and inactivated in vivo, with active site Tyr34 as the key oxidatively modified residue. We previously reported a k of ∼1.0 × 105 M–1 s–1 for the reaction of hMnSOD with ONOO by direct stopped-flow spectroscopy and the critical role of Mn in the nitration process. In this study, we further established the mechanism of the reaction of hMnSOD with ONOO, including the necessary re-examination of the second-order rate constant by an independent method and the delineation of the microscopic steps that lead to the regio-specific nitration of Tyr34. The redetermination of k was performed by...  Read more