The density functional code deMon2k employs a fitted density throughout (Auxiliary Density Functional Theory), which offers a great speed advantage without sacrificing necessary accuracy. Powerful Quantum Mechanical/Molecular Mechanical (QM/MM) approaches are reviewed. Following an overview of the basic features of deMon2k that make it efficient while retaining accuracy, three QM/MM implementations are compared and contrasted. In the first, deMon2k is interfaced with the CHARMM MM code (CHARMM-deMon2k); in the second MM is coded directly within the deMon2k software; and in the third the Chemistry in Ruby (Cuby) wrapper is used to drive the calculations. Cuby is also used in the context of constrained-DFT/MM calculations. Each of these implementations is described briefly; pros and cons are discussed and a few recent applications are described briefly. Applications include solvated ions and biomolecules, polyglutamine peptides important in polyQ neurodegenerative diseases, copper monooxygenases and ultra-rapid electron transfer in cryptochromes.

Frontiers in Computational Chemistry presents contemporary research on molecular modeling techniques used in drug discovery and the drug development process: computer aided molecular design, drug discovery and development, lead generation, lead optimization, database management, computer and molecular graphics, and the development of new computational methods or efficient algorithms for the simulation of chemical phenomena including analyses of biological activity. The sixth volume of this series features these six different perspectives on the application of computational chemistry in rational drug design: 1. Computer-aided molecular design in computational chemistry 2. The role of ensemble conformational sampling using molecular docking & dynamics in drug discovery 3. Molecular dynamics applied to discover antiviral agents 4. Pharmacophore modeling approach in drug discovery against the tropical infectious disease malaria 5. Advances in computational network pharmacology for Traditional Chinese Medicine (TCM) research 6. Progress in electronic-structure based computational methods: from small molecules to large molecular systems of biological significance

The growth of computational power, provided by new hardware technologies and the development of better theoretical methods and algorithms, allows more than ever an improvement in the reliability of computational predictions in medical sciences, along with a better understanding of the underlying molecular mechanisms. However, one limitation of computational chemistry approaches in the field of biological systems is the complexity of the molecules and the environment in which such molecules are to be studied. Important issues such as the determination of molecular properties which depend on the electronic structure face a considerable challenge when all-electron methodologies are required in the investigation. The most rigorous and sophisticated electronic structure methodologies, like density functional theory (DFT), are usually overwhelmed by the molecular size of most pharmacological targets. However, important implementations were recently achieved by the developers group of the computational chemistry code deMon2k. Knowing that the computation of electrostatic interaction integrals is an important bottleneck in all-electron calculations three new implementations have been worked out in order to eliminate such bottleneck. These implementations allow deMon2k now to explore biological and pharmacological systems in the framework of all-electron DFT methodologies.

In spite of significant experimental effort dedicated to the study of Cu(2+) binding to the amyloid beta (Aβ) peptide, involved in Alzheimer's disease, the nature of the oxygen-based ligand in the low pH component of the Cu(2+)-Aβ(1-16) complex is still under debate. This study reports density-functional-theory-based calculations that explore the potential energy surface of Cu(2+) complexes including N and O ligands at the N-terminus of the Aβ peptide, with a focus on evaluating the role of Asp1 carboxylate in copper coordination. Model conformers including 3, 6, and 17 amino acids have been used to systematically study several aspects of the Cu(2+)-coordination such as the Asp1 side chain conformation, local peptide backbone geometry, electrostatic and/or hydrogen bond interactions, and number and availability of Cu(2+) ligands. Our results show that the Asp1 peptide carbonyl binds to Cu(2+) only if the coordination number is less than four. In contrast, if four ligands are available, the most stable structures include the Asp1 carboxylate in equatorial position instead of the Asp1 carbonyl group. The two lowest energy Cu(2+)-Aβ(1-17) models involve Asp1 COO(-), the N-terminus, and His6 and His14 as equatorial ligands, with either a carbonyl or a water molecule in the axial position. These models are in good agreement with experimental data reported for component I of the Cu(2+)-Aβ(1-16) complex, including EXAFS- and X-ray-derived Cu(2+)-ligand distances, Cu(2+) EPR parameters, and (14)N and (13)C superhyperfine couplings. Our results suggest that at low pH, Cu(2+)-Aβ species with Asp1 carboxylate equatorial coordination coexist with species coordinating the Asp1 carbonyl. Understanding the bonding mechanism in these species is relevant to gain a deeper insight on the molecular processes involving copper-amyloid-β complexes, such as aggregation and redox activity.

The development of molecular density functional theory (DFT) methods has considerably simplified the calculation of large molecules, including transition metal clusters. This has also attracted the attention of coordination chemists to this technique. In this chapter we give a brief description of the computational methodologies implemented in the DFT program deMon2k.

Density Functional Theory (DFT) has become the workhorse of applied computational chemistry. DFT has grown in a number of different directions depending on the applications concerned. In this chapter, we provide a broad review of a number of DFT and DFT-based methods, having in mind the accurate description of biological systems and processes. These range from pure "cluster" DFT studies of the structure, properties, and reactions of biochemical species (such as enzymatic catalysts) using either straight DFT or dispersion-corrected functionals (DFT-D), to Born-Oppenheimer-DFT dynamics of systems containing up to a hundred atoms or more (such as glycero-lipids), to hybrid DFT/Molecular Mechanical Molecular Dynamics methods which include protein and solvent environments (for enzymes or ion channels, for example), to constrained-DFT (working within the Marcus framework for electron-transfer reactions), to Interpretational-DFT (which provides the interpretational benefits of the Kohn-Sham DFT methodology).

BornOppenheimer molecular dynamics (BOMD) in combination with density functional theory, augmented with a damped empirical dispersion term, has been used to study the behavior of dilauroyl phosphatidylcholine (DLPC) isomers with temperature. In contrast to dimyristoyl phosphatidylcholine (DMPC), the BOMD results show the presence of various conformations at different temperatures. The molecular orderdisorder process, quantified by the distance-fluctuation criterion as a function of temperature, is characterized by two transitions. This is in line with the known two-phase transitions of DLPC bilayers, involving trans to gauche conformational changes in the alkane chains. The different temperature dependence of the DLPC and DMPC molecules suggests that the experimentally observed unusual dynamics of DLPC bilayers compared to that of longer chain lipids is governed to a large extent by the intramolecular dynamics. A first-principles methodology applied at the molecular level can thus be an appropriate tool for microscopic analysis of the orderdisorder transitions, which are related to the molecular structural transformations within large assemblies. (C) 2012 Wiley Periodicals, Inc.

This paper highlights the relevance of including the high-energy conformational states sampled by Born-Oppenheimer molecular dynamics (BOMD) in the calculation of time-averaged NMR chemical shifts. Our case study is the very flexible glycerol molecule that undergoes interconversion between conformers in a nonrandom way. Along the sequence of structures from one backbone conformer to another, transition states have been identified. The three (13)C NMR chemical shifts of the molecule were estimated by averaging their calculated values over a large set of BOMD snapshots. The simulation time needed to obtain a good agreement with the two signals present in the experimental spectrum is shown to be dependent on the atomic orbital basis set used for the dynamics, with a necessary longer trajectory for the most extended basis sets. The large structural deformations with respect to the optimized conformer geometries that occur along the dynamics are related to a kinetically driven conformer distribution. Calculated conformer type populations are in good agreement with experimental gas phase microwave results.

Structural and magnetic properties of one anionic and one cationic amphiphile molecule (sodium octanoate and hexadecyltrimethylammonium chloride, respectively) in water are studied comparing different methods to account for the presence of the solvent. Calculated 13C NMR chemical shifts are used as the probe for accuracy of the theoretical electronic structures obtained with different descriptions of the surfactants in water solution. The best agreement with the experimental data are obtained by averaging 13C NMR isotropic chemical shifts over a large number of conformational structures of sodium octanoate while considering the electronic structure of the solvent molecules. The 13C chemical shift values of the hexadecyltrimethylammonium alkane chain are systematically overestimated by 10–15 ppm even if an extensive conformational sampling and water as the polarized continuum medium have been taken into consideration. The role of the basis set quality has been studied and discussed as well.

This article provides a brief overview of the quantum chemical auxiliary density functional theory program deMon2k. A basic introduction into its key computational features is given. By selected examples, it is shown how deMon2k can contribute to the elucidation of problems in chemistry, biology, and materials science such as finite temperature effects, nuclear magnetic resonance studies, structure determinations, heterogeneous, and enzymatic catalysis. (C) 2011 John Wiley & Sons, Ltd.

Small probe molecules like CO and CH3CN are used to estimate the acid strength of Bronsted sites in mordenite (H-MOR) models, depending on their framework location, main channel (MC) or side pocket (SP). Adsorption strength on Bronsted sites has often been correlated with the concept of confinement, smaller cavities being considered as catalytically more active. In this work, we show that, at zero coverage (1 molecule per site, per cavity), the host guest energetic interactions do not depend on the cavity volumes, leading to similar adsorption energies for MC and SP sites. This unexpected result is in agreement with recent experimental studies which show that confinement is more related with higher concentration of host molecules in small rather than large cavities at high pressure.

In the context of nanomedicine, liposils (liposomes and silica) have a strong potential for drug storage and release schemes: such materials combine the intrinsic properties of liposome (encapsulation) and silica (increased rigidity, protective coating, pH degradability). In this work, an original approach combining solid state NMR, molecular dynamics, first principles geometry optimization, and NMR parameters calculation allows the building of a precise representation of the organic/inorganic interface in liposils. {(1)H-(29)Si}(1)H and {(1)H-(31)P}(1)H Double Cross-Polarization (CP) MAS NMR experiments were implemented in order to explore the proton chemical environments around the silica and the phospholipids, respectively. Using VASP (Vienna Ab Initio Simulation Package), DFT calculations including molecular dynamics, and geometry optimization lead to the determination of energetically favorable configurations of a DPPC (dipalmitoylphosphatidylcholine) headgroup adsorbed onto a hydroxylated silica surface that corresponds to a realistic model of an amorphous silica slab. These data combined with first principles NMR parameters calculations by GIPAW (Gauge Included Projected Augmented Wave) show that the phosphate moieties are not directly interacting with silanols. The stabilization of the interface is achieved through the presence of water molecules located in-between the head groups of the phospholipids and the silica surface forming an interfacial H-bonded water layer. A detailed study of the (31)P chemical shift anisotropy (CSA) parameters allows us to interpret the local dynamics of DPPC in liposils. Finally, the VASP/solid state NMR/GIPAW combined approach can be extended to a large variety of organic-inorganic hybrid interfaces.

In this chapter, techniques and methods for the structure determination of clusters are reviewed with emphasis on how the combination of experimental data and the results of quantum chemical calculations can lead to a reliable and accurate description of the electronic and geometrical structure of clusters. After a review of density functional theory methods used for the calculation of molecular properties, the basic principles and features of current experimental techniques for the analysis of clusters are discussed in the first section. The next section describes in detail, on the basis of a variety of examples, the possibility of combining experimental and theoretical results in order to obtain structural information for clusters. Special attention is paid to the question of how experimental data and the results of quantum chemical calculations can be compared, how the information obtained via experiment and theory complement each other, and what degree of agreement between theory and experiment can be expected. This leads to the final section, where the necessary experimental conditions and improvements of theoretical models and methods are summarized with the aim to achieve a better match between experimental and theoretical results, and to thus gain a deeper insight into the structural properties of clusters.

Lysobisphosphatidic acid (LBPA), or bis(monoacylglycerol)phosphate, is a very interesting lipid, that is mainly found in late endosomes. It has several intriguing characteristics, which differ from those of other animal glycerophospholipids, that may be related to its specific functions, particularly in the metabolism of cholesterol. Its phosphodiester group is bonded at the sn-1 (sn-1') positions of the glycerols rather than at sn-3 (sn-3'); the position of the two fatty acid chains is still under debate but, increasingly, arguments favor the sn-2, sn-2' position in the native molecule, whereas isolation procedures or acidic conditions lead to the thermodynamically more stable sn-3, sn-3' structure. Because of these peculiar features, it can be expected that LBPA shape and interactions with membrane lipids and proteins are related to its structure at the molecular level. We applied quantum mechanical methods to study the structures and stabilities of the 2,2' and 3,3' LBPA isomers, using a step-by-step procedure from glycerol to precursors (in vitro syntheses) and to the final isoforms. The structures of the two positional LBPA isomers are substantially different, showing that the binding positions of the fatty acid chains on the glycerol backbone determine the shape of the LBPA molecule and thus, possibly, its functions. The 3,3' LBPA structures obtained are more stable with respect to the 2,2' form, as expected from experiment. If one argues that the in vivo synthesis starts from the present glycerol conformers and considering the most stable bis(glycero)phosphate structures, the 2,2' isoform should be the most probable isomer.

The density functional based tight binding (DFTB) is a semiempirical method derived from the density functional theory (DFT). It inherits therefore its problems in treating van der Waals clusters. A major error comes from dispersion forces, which are poorly described by commonly used DFT functionals, but which can be accounted for by an a posteriori treatment DFT-D. This correction is used for DFTB. The self-consistent charge (SCC) DFTB is built on Mulliken charges which are known to give a poor representation of Coulombic intermolecular potential. We propose to calculate this potential using the class IV/charge model 3 definition of atomic charges. The self-consistent calculation of these charges is introduced in the SCC procedure and corresponding nuclear forces are derived. Benzene dimer is then studied as a benchmark system with this corrected DFTB (c-DFTB-D) method, but also, for comparison, with the DFT-D. Both methods give similar results and are in agreement with references calculations (CCSD(T) and symmetry adapted perturbation theory) calculations. As a first application, pyrene dimer is studied with the c-DFTB-D and DFT-D methods. For coronene clusters, only the c-DFTB-D approach is used, which finds the sandwich configurations to be more stable than the T-shaped ones.

The structures and stabilities of the glycerol (G) and glycerol 3-phosphate (G3P) isomers have been calculated in the gas phase, using an ab initio density functional theory (DFT) method. The different conformational structures are shown to be at the origin of the various phospholipid conformers, except, obviously, for the alkyl chain torsions. The G3P conformations have been examined taking into account the experimental structures of the complexation sites in the glycerol kinase (GK) and glycerol 3-phosphate acyl transferase (G3PAT) enzymes, which correspond to the first and second steps of the "de novo" phospholipid biogenesis, respectively. The conformational analysis of the glycerophosphate skeleton is shown to determine most of the structural characteristics of the phosphatidyl choline lipids, which differ by the length of their diacyl chains, i.e., dilauroyl (DL), dimyristoyl (DM), and dipalmitoyl (DP) phosphatidylcholines (PC). Higher energy conformers with kinks in the acyl chains have been found, in preparation for molecular dynamics studies of the chain melting phase transformation.