: The unpolarized absorption and circular dichroism spectra of the fundamental vibrational transitions of the chiral molecule, 4-methyl-2-oxetanone, are calculated ab initio. Harmonic force fields are obtained using Density Functional Theory (DFT), MP2, and SCF methodologies and a 5S4P2D/3S2P (TZ2P) basis set. DFT calculations use the Local Spin Density Approximation (LSDA), BLYP, and Becke3LYP (B3LYP) density functionals. Mid-IR spectra predicted using LSDA, BLYP, and B3LYP force fields are of significantly different quality, the B3LYP force field yielding spectra in clearly superior, and overall excellent, agreement with experiment. The MP2 force field yields spectra in slightly worse agreement with experiment than the B3LYP force field. The SCF force field yields spectra in poor agreement with experiment.The basis set dependence of B3LYP force fields is also explored: the 6-31G* and TZ2P basis sets give very similar results while the 3-21G basis set yields spectra in substantially worse agreements with experiment. jg

Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields

Molecular recognition in biological systems relies on the existence of specific attractive interactions between two partner molecules. Structure-based drug design seeks to identify and optimize such interactions between ligands and their host molecules, typically proteins, given their three-dimensional structures. This optimization process requires knowledge about interaction geometries and approximate affinity contributions of attractive interactions that can be gleaned from crystal structure and associated affinity data.

Here we compile and review the literature on molecular interactions as it pertains to medicinal chemistry through a combination of careful statistical analysis of the large body of publicly available X-ray structure data and experimental and theoretical studies of specific model systems. We attempt to extract key messages of practical value and complement references with our own searches of the CSDa,(1) and PDB databases.(2) The focus is on direct contacts between ligand and protein functional groups, and we restrict ourselves to those interactions that are most frequent in medicinal chemistry applications. Examples from supramolecular chemistry and quantum mechanical or molecular mechanics calculations are cited where they illustrate a specific point. The application of automated design processes is not covered nor is design of physicochemical properties of molecules such as permeability or solubility.

Throughout this article, we wish to raise the readers’ awareness that formulating rules for molecular interactions is only possible within certain boundaries. The combination of 3D structure analysis with binding free energies does not yield a complete understanding of the energetic contributions of individual interactions. The reasons for this are widely known but not always fully appreciated. While it would be desirable to associate observed interactions with energy terms, we have to accept that molecular interactions behave in a highly nonadditive fashion.3,4 The same interaction may be worth different amounts of free energy in different contexts, and it is very hard to find an objective frame of reference for an interaction, since any change of a molecular structure will have multiple effects. One can easily fall victim to confirmation bias, focusing on what one has observed before and building causal relationships on too few observations. In reality, the multiplicity of interactions present in a single protein−ligand complex is a compromise of attractive and repulsive interactions that is almost impossible to deconvolute. By focusing on observed interactions, one neglects a large part of the thermodynamic cycle represented by a binding free energy: solvation processes, long-range interactions, conformational changes. Also, crystal structure coordinates give misleadingly static views of interactions. In reality a macromolecular complex is not characterized by a single structure but by an ensemble of structures. Changes in the degrees of freedom of both partners during the binding event have a large impact on binding free energy.

The text is organized in the following way. The first section treats general aspects of molecular design: enthalpic and entropic components of binding free energy, flexibility, solvation, and the treatment of individual water molecules, as well as repulsive interactions. The second half of the article is devoted to specific types of interactions, beginning with hydrogen bonds, moving on to weaker polar interactions, and ending with lipophilic interactions between aliphatic and aromatic systems. We show many examples of structure−activity relationships; these are meant as helpful illustrations but individually can never confirm a rule.

http://pubs.acs.org/doi/pdf/10.1021/jm100112j

A Medicinal Chemist’s Guide to Molecular Interactions

Lung Wa Chung,† W. M. C. Sameera,‡ Romain Ramozzi,‡ Alister J. Page, Miho Hatanaka,‡ Galina P. Petrova, Travis V. Harris,‡,⊥ Xin Li, Zhuofeng Ke, Fengyi Liu, Hai-Bei Li, Lina Ding, and Keiji Morokuma*,‡ †Department of Chemistry, South University of Science and Technology of China, Shenzhen 518055, China ‡Fukui Institute for Fundamental Chemistry, Kyoto University, 34-4 Takano Nishihiraki-cho, Sakyo, Kyoto 606-8103, Japan Newcastle Institute for Energy and Resources, The University of Newcastle, Callaghan 2308, Australia Faculty of Chemistry and Pharmacy, University of Sofia, Bulgaria Boulevard James Bourchier 1, 1164 Sofia, Bulgaria Department of Chemistry, State University of New York at Oswego, Oswego, New York 13126, United States State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China Key Laboratory of Macromolecular Science of Shaanxi Province, School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi’an, Shaanxi 710119, China School of Ocean, Shandong University, Weihai 264209, China School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China

The ONIOM Method and Its Applications

Water molecules confined to nonpolar pores and cavities of nanoscopic dimensions exhibit highly unusual properties. Water filling is strongly cooperative, with the possible coexistence of filled and empty states and sensitivity to small perturbations of the pore polarity and solvent conditions. Confined water molecules form tightly hydrogen-bonded wires or clusters. The weak attractions to the confining wall, combined with strong interactions between water molecules, permit exceptionally rapid water flow, exceeding expectations from macroscopic hydrodynamics by several orders of magnitude. The proton mobility along 1D water wires also substantially exceeds that in the bulk. Proteins appear to exploit these unusual properties of confined water in their biological function (e.g., to ensure rapid water flow in aquaporins or to gate proton flow in proton pumps and enzymes). The unusual properties of water in nonpolar confinement are also relevant to the design of novel nanofluidic and molecular separation devices or fuel cells.

/pdf/water-in-nonpolar-confinement-from-nanotubes-to-proteins-and-412uecrowv.pdf

Water in Nonpolar Confinement: From Nanotubes to Proteins and Beyond *

Complex (dusty) plasmas are composed of a weakly ionized gas and charged microparticles and represent the plasma state of soft matter. Complex plasmas have several remarkable features: Dynamical time scales associated with microparticles are ``stretched'' to tens of milliseconds, yet the microparticles themselves can be easily visualized individually. Furthermore, since the background gas is dilute, the particle dynamics in strongly coupled complex plasmas is virtually undamped, which provides a direct analogy to regular liquids and solids in terms of the atomistic dynamics. Finally, complex plasmas can be easily manipulated in different ways---also at the level of individual particles. Altogether, this gives us a unique opportunity to go beyond the limits of continuous media and study---at the kinetic level---various generic processes occurring in liquids or solids, in regimes ranging from the onset of cooperative phenomena to large strongly coupled systems. In the first part of the review some of the basic and new physics are highlighted which complex plasmas enable us to study, and in the second (major) part strong coupling phenomena in an interdisciplinary context are examined. The connections with complex fluids are emphasized and a number of generic liquid and solid-state issues are addressed. In summary, application oriented research is discussed.

Complex plasmas: An interdisciplinary research field

We explore the structure and thermodynamics of water clusters confined in nonpolar cavities. By calculating the grand-canonical partition function term by term, we show that small nonpolar cavities can be filled at equilibrium with highly structured water clusters. The structural and thermodynamic properties of these encapsulated water clusters are similar to those observed experimentally in the gas phase. Water filling is highly sensitive to the size of the cavity and the strength of the interactions with the cavity wall. Water penetration into pores can thus be modulated by small changes in the polarity and structure of the cavity. Implications on water penetration into proteins are discussed.

https://www.pnas.org/content/pnas/101/49/17002.full.pdf

Water clusters in nonpolar cavities.

Water molecules in the narrow cylindrical pore of a (6,6) carbon nanotube form single-file chains with their dipoles collectively oriented either up or down along the tube axis. We study the interaction of such water chains with homogeneous electric fields for finite closed and infinite periodically replicated tubes. By evaluating the grand-canonical partition function term-by-term, we show that homogeneous electric fields favor the filling of previously empty nanotubes with water from the bulk phase. A two-state description of the collective water dipole orientation in the nanotube provides an excellent approximation for the dependence of the water-chain polarization and the filling equilibrium on the electric field. The energy and entropy contributions to the free energy of filling the nanotube were determined from the temperature dependence of the occupancy probabilities. We find that the energy of transfer depends sensitively on the water-tube interaction potential, and that the entropy of one-dimensionally ordered water chains is comparable to that of bulk water. We also discuss implications for proton transfer reactions in biology.

Electric field and temperature effects on water in the narrow nonpolar pores of carbon nanotubes.

Transition state search is at the center of multiple types of computational chemical predictions related to mechanistic investigations, reactivity and regioselectivity predictions, and catalyst design The process of finding transition states in practice is, however, a laborious multistep operation that requires significant user involvement Here, we report a highly automated workflow designed to locate transition states for a given elementary reaction with minimal setup overhead The only essential inputs required from the user are the structures of the separated reactants and products The seamless workflow combining computational technologies from the fields of cheminformatics, molecular mechanics, and quantum chemistry automatically finds the most probable correspondence between the atoms in the reactants and the products, generates a transition state guess, launches a transition state search through a combined approach involving the relaxing string method and the quadratic synchronous transit, and fi

Automated Transition State Search and Its Application to Diverse Types of Organic Reactions

Molecular dynamics simulations of water at 298 K and 1 atm of pressure are used to investigate the electric-field dependence of the density and polarization density of water between two graphite-like plates of different sizes (9.8 x 9.2 and 17.7 x 17.2 A) in an open system for plate separations of 8.0, 9.5, and 16.4 A. The interactions with water were tuned to "hard-wall-like" and "normal" C-O hydrophobic potentials. Water between the larger plates at 16.4 A separation is layered but is metastable with respect to capillary evaporation at zero field (Bratko, D.; Curtis, R. A.; Blanch, H. W.; Prausnitz, J. M. J. Chem. Phys. 2001, 115, 3873). Applying a field decreases the density of the water between the plates, in apparent contradiction to thermodynamic and integral equation theories of bulk fluid electrostriction that ignore surface effects, rendering them inapplicable to finite-sized films of water between hydrophobic plates. This suggests that the free energy barrier for evaporation is lowered by the applied field. Water, between "hard-wall-like" plates at narrower separations of 9.5 A and less, shows a spontaneous but incomplete evaporation at zero field within the time scale of our simulation. Evaporation is further enhanced by an electric field. No such evaporation occurs, on these time scales, for the smaller plates with the "hard-wall-like" potential at a separation of 8.0 A at zero field, signaling a crossover in behavior as the plate dimension decreases, but the water density still diminishes with increasing field strength. These observations could have implications for the behavior of thin films of water between surfaces in real physical and biological systems.

Water between Plates in the Presence of an Electric Field in an Open System

Confinement effects on protein stability are relevant in a number of biological applications ranging from encapsulation in the cylindrical cavity of a chaperonin, translocation through pores, and structure formation in the exit tunnel of the ribosome. Consequently, free energies of interaction between amino acid side chains in restricted spaces can provide insights into factors that control protein stability in nanopores. Using all-atom molecular dynamics simulations, we show that 3 pair interactions between side chains--hydrophobic (Ala-Phe), polar (Ser-Asn) and charged (Lys-Glu)--are substantially altered in hydrophobic, water-filled nanopores, relative to bulk water. When the pore holds water at bulk density, the hydrophobic pair is strongly destabilized and is driven to large separations corresponding to the width and the length of the cylindrical pore. As the water density is reduced, the preference of Ala and Phe to be at the boundary decreases, and the contact pair is preferred. A model that accounts for the volume accessible to Phe and Ala in the solvent-depleted region near the pore boundary explains the simulation results. In the pore, the hydrogen-bonded interactions between Ser and Asn have an enhanced dependence on their relative orientations, as compared with bulk water. When the side chains of Lys and Glu are restrained to be side by side, parallel to each other, then salt bridge formation is promoted in the nanopore. Based on these results, we argue and demonstrate that for a generic amphiphilic sequence, cylindrical confinement is likely to enhance thermodynamic stability relative to the bulk.

http://biotheory.umd.edu/PDF/Vaithee_PNAS_2008.pdf

S. Vaitheeswaran

Papers

Water clusters in nonpolar cavities.

Electric field and temperature effects on water in the narrow nonpolar pores of carbon nanotubes.

Automated Transition State Search and Its Application to Diverse Types of Organic Reactions

Water between Plates in the Presence of an Electric Field in an Open System

Interactions between amino acid side chains in cylindrical hydrophobic nanopores with applications to peptide stability