How Water's Properties Are Encoded in Its Molecular Structure and Energies.

How are water's material properties encoded within the structure of the water molecule? This is pertinent to understanding Earth's living systems, its materials, its geochemistry and geophysics, and a broad spectrum of its industrial chemistry. Water has distinctive liquid and solid properties: It is highly cohesive. It has volumetric anomalies-water's solid (ice) floats on its liquid; pressure can melt the solid rather than freezing the liquid; heating can shrink the liquid. It has more solid phases than other materials. Its supercooled liquid has divergent thermodynamic response functions. Its glassy state is neither fragile nor strong. Its component ions-hydroxide and protons-diffuse much faster than other ions. Aqueous solvation of ions or oils entails large entropies and heat capacities. We review how these properties are encoded within water's molecular structure and energies, as understood from theories, simulations, and experiments. Like simpler liquids, water molecules are nearly spherical and interact with each other through van der Waals forces. Unlike simpler liquids, water's orientation-dependent hydrogen bonding leads to open tetrahedral cage-like structuring that contributes to its remarkable volumetric and thermal properties

Multiscale Geometric Modeling of Macromolecules I: Cartesian Representation

This paper focuses on the geometric modeling and computational algorithm development of biomolecular structures from two data sources: Protein Data Bank (PDB) and Electron Microscopy Data Bank (EMDB) in the Eulerian (or Cartesian) representation. Molecular surface (MS) contains non-smooth geometric singularities, such as cusps, tips and self-intersecting facets, which often lead to computational instabilities in molecular simulations, and violate the physical principle of surface free energy minimization. Variational multiscale surface definitions are proposed based on geometric flows and solvation analysis of biomolecular systems. Our approach leads to geometric and potential driven Laplace–Beltrami flows for biomolecular surface evolution and formation. The resulting surfaces are free of geometric singularities and minimize the total free energy of the biomolecular system. High order partial differential equation (PDE)-based nonlinear filters are employed for EMDB data processing. We show the efficacy of this approach in feature-preserving noise reduction. After the construction of protein multiresolution surfaces, we explore the analysis and characterization of surface morphology by using a variety of curvature definitions. Apart from the classical Gaussian curvature and mean curvature, maximum curvature, minimum curvature, shape index, and curvedness are also applied to macromolecular surface analysis for the first time. Our curvature analysis is uniquely coupled to the analysis of electrostatic surface potential, which is a by-product of our variational multiscale solvation models. As an expository investigation, we particularly emphasize the numerical algorithms and computational protocols for practical applications of the above multiscale geometric models. Such information may otherwise be scattered over the vast literature on this topic. Based on the curvature and electrostatic analysis from our multiresolution surfaces, we introduce a new concept, the polarized curvature, for the prediction of protein binding sites

Chemical dynamics

CHEMICAL EDUCATION is changing rapidly, not only because of the explosive growth of knowledge but also because the new knowledge has stimulated reformulation of working principles in the science. Undergraduate curricula and individual courses are in constant flux. Nowhere is the change and challenge greater than in freshman chemistry. Teachers of freshmen must meet the intellectual needs of students who have had more sophisticated and stimulating high school courses than those given a decade ago. At the same time, the freshman teacher must be aware of the constant modification of the more advanced courses in chemistry and other fields that his students will study later. Continuous reformulation of courses sometimes results in the inclusion of valuable new material at the expense of other equally valuable material. We believe that this has happened in some of the sophisticated courses in freshman chemistry. Structural chemistry often receives far greater emphasis than chemical dynamics. In 1965, the Westheimer Report (Chemistry: Opportunities and Needs, National Academy of Sciences, 1965) identified the three major fields of chemistry as structure, dynamics, and synthesis. We firmly believe that a balanced course in general chemistry should reflect the outlook of this report. The study of modern chemical synthesis is too demanding to be covered in depth in an introductory course. However, chemical dynamics -- the systematic study of reactions and reactivity -- can and should be studied at the freshman level. The study of changing chemical systems is the most fascinating part of the field for many students, and its early introduction forms a solid foundation for later study. This small volume is our attempt to answer the need. The book is intended for students who have had introductory stoichiometry, energetics, and structure at the level of a modern freshman textbook (for example, Basic Principles of Chemistry, by H. B. Gray and G. P. Haight, Jr., W. A. Benjamin, Inc., New York, 1961). Chemical Dynamics is designed to accompany approximately 20-25 lectures to be given as the concluding section of a freshman chemistry course. We have chosen topics for their fundamental importance in dynamics and then tried to develop a presentation suitable for freshman classes. Discussion of each topic is limited, because chemistry majors will inevitably return to all the subject matter in more advanced courses. We hope that the following ideas have been introduced with a firm conceptual basis and in enough detail for the student to apply them to chemical reality. 1. Thermodynamics and kinetics are two useful measures of reactivity. 2. Characteristic patterns of reactivity are systematically related to molecular geometry and electronic structure. 3. Reaction mechanisms are fascinating in their own right and indispensable for identification of significant problems in reaction rate theory. 4. The concepts underlying experiments with elementary reaction processes (molecular beams) are simple, even though the engineering of the experiments is complicated. 5. Application of theories of elementary reaction rates to most reactions (slow reactions, condensed media, etc.) provides enough challenge to satisfy the most ambitious young scientist. The book includes exercises at the end of each chapter except the last. Their purpose is didactic, inasmuch as most have been written with the aim of strengthening a particular point emphasized in the chapter, or of introducing an important topic which was not developed in the text for reasons of space and which would normally be taken up in greater detail in later courses. The material in this volume has been adapted primarily from a portion of the lectures given by H.B.G. and G.S.H. to the Chemistry 2 students at the California Institute of Technology during the academic years 1966-1967 and 1967-1968. These lectures were taped, written up by J.B.D., and distributed to the students in the form of class notes. The final manuscript was written after class-testing of the notes. Our decision to revise the Chemistry 2 notes in the form of an introductory text was made after H.B.G. and G.S.H. participated in the San Clemente Chemical Dynamics Conference, held in December 1966 under the sponsorship of the Advisory Council of College Chemistry. At San Clemente we found we were not the only group concerned over the exclusion of significant reference to chemical reactions and reactivity relationships in freshman courses. In addition to their general encouragement, which provided the necessary additional impetus, these colleagues prepared a series of papers for publication in an issue of the Journal of Chemical Education. It is a pleasure to acknowledge here the direct contribution these papers made in shaping the final form of our volume; specifically, in preparing Chapter 6, we have drawn examples from the San Clemente papers of Professors R. Marcus, A. Kuppermann and E. F. Greene, and J. Halpern. The concluding chapter of this book was developed from the lectures given by Professors E. F. Greene (dynamics in simple systems), Richard Wolfgang (atomic carbon), John D. Roberts (nuclear magnetic resonance), and F. C. Anson (electrochemical dynamics) to the students of Chemistry 2 in May 1967. These colleagues have kindly given us permission to use their material. We are grateful to Professors Ralph G. Pearson and Paul Haake, who read the entire manuscript and offered valuable criticism. It is a special pleasure to acknowledge the enormous contribution our students in Chemistry 2 made to the project. Their enthusiastic, critical attitude helped us make many improvements in the manuscript. Thanks are also due to four very special members of the staff of W. A. Benjamin, Inc., for seeing this project through with infectious vigor. Finally, and not the least, we acknowledge the role Susan Brittenham and Eileen McKoy played in preparing the final manuscript. JOSEPH B. DENCE HARRY B. GRAY GEORGE S. HAMMOND Pasadena, California January 196

Prediction of partition coefficients for systems of micelles using DFT

[eng] A compound’s solvent−water partition coefficient (log P) measures the equilibrium ratio of the compound’s concentrations in a two-phase system: as two solvents in contact or a system of micelles in an aqueous solution. In this thesis, the partition coefficient of three groups of small compounds (alcohol, ether, and hydrocarbons) in 10 different solvents (benzene, cyclohexane, hexane, n-Octane, toluene, carbon tetrachloride, heptane, trichloroethane, and octanol) was computed used DFT and B3LYP method with 6.31G(d), 6.311+G** and 6.311++G** basis sets. It is obtained that the partition coefficient of alcohol solutes in various solvents using the 6.31G(d) basis set indicates a satisfactory correlation with experimental values. The correlation between the experimental value and the partition coefficient of ether solutes in different solvents using the 6.311++G** basis set shows high agreement. The experimental data displayed a high correlation with the partition coefficient computed for hydrocarbon compounds in various solvents using all three basis sets: 6.31G(d), 6.311+G**, and 6.311++G**. In addition, we have studied the correlation of the experimental partition coefficients in Sodium Dodecyl Sulfate (SDS), Hexadecyltrimethylammonium bromide (HTAB), Sodium cholate (SC), and Lithium perfluoro octane sulfonate (LPFOS) micelles with ab initio calculated partition coefficients in 15 different organic solvents. Specifically, the partition coefficients of a series of 63 molecules in an aqueous system of SDS, SC, HTAB, and LPFOS micelles are correlated with the partition coefficient in heptane/water, cyclohexane/water, n-dodecane/water, pyridine/water, acetic acid/water, octanol/water, acetone/water, 1-propanol/water, 2-propanol/water, methanol/water, formic acid/water, diethyl sulfide/water, decan-1-ol/water, 1-2 ethane diol/water and dimethyl sulfoxide/water systems. All calculations were performed using the Gaussian 16 Quantum Chemistry package. Molecular structures were generated in the more extended conformation using Avogadro, and geometries of all molecules were optimized using Density Functional Theory (DFT) B3LYP and MO6-2X with 6-31++G** basis set by the continuum solvation model based on density (SMD). The obtained results show that calculated partition coefficients in the alcohol/water mixture give the best correlation to predict the experimental partition coefficients in SDS, SC, and LPFOS micelles. With respect to HTAB micelle systems, a new selection of molecules is created, excluding those containing N atoms and Urea atom groups. Interestingly, the partition coefficient of these chosen molecules exhibits a strong correlation with the experimental partition coefficient. Finally, the partition coefficient of flexible molecules was studied by the same protocol for two solvent combinations, octanol/water and cyclohexane/water. The calculated values were compared with the experimental partition coefficients. The average partition coefficient in octanol solvent exhibited a high correlation with the experimental data. However, for the 16 compounds in the cyclohexane solvent, their partition coefficients do not exhibit significant agreement with the experimental partition coefficients.[cat] S'ha desenvolupat una metodologia computacional per calcular el coeficient de partició de diferents tipus de molècules en sistemes micel·lars. En primer lloc, s'ha calculat el coeficient de partició de tres grups de compostos (alcohol, èter i hidrocarburs) utilitzant el mètode DFT amb el funcional B3LYP. S'han obtingut correlacions satisfactòries amb els valors experimentals. En aquesta tesi s'ha desenvolupat un procediment per calcular els coeficients de partició experimentals en micel·les de dodecilsulfat de sodi (SDS), bromur d'hexadeciltrimetilamoni (HTAB), colat de sodi (SC) i perfluorooctanosulfonat de liti (LPFOS). Específicament, els coeficients de partició d'una sèrie de 63 molècules en un sistema aquós de micel·les de SDS, SC, HTAB i LPFOS es correlacionen amb el coeficient de partició en deu barreges aquoses. Els resultats obtinguts mostren que els coeficients de partició calculats a la barreja alcohol/aigua donen la millor correlació per predir els coeficients de partició experimentals en micel·les SDS, SC i LPFOS. Pel que fa als sistemes micelars HTAB, es crea una nova selecció de molècules, excloent-ne aquelles que contenen àtoms de N aromàtics i grups d'urea. És interessant notar que el coeficient de partició d'aquestes molècules triades mostra una forta correlació amb el coeficient de partició experimental. Finalment, es va estudiar el coeficient de partició de molècules flexibles mitjançant el mateix protocol per a dues combinacions de dissolvents, octanol/aigua i ciclohexà/aigua. Els valors calculats es van comparar amb els coeficients de partició experimentals. El coeficient de partició mitjana en dissolvent octanol va mostrar una alta correlació amb les dades experimentals. Tot i això, per als 16 compostos en el dissolvent ciclohexà, els seus coeficients de partició no mostren una concordança significativa amb els coeficients de partició experimental

Characterization and exploitation of protein ligand interactions for structure based drug design

Most characterised protein-small molecule interactions that display a change in heat capacity (\bigtriangleupCp) occur with a negative \bigtriangleupCp value. This is often attributed to solvent reorganisation from reduction in solvent accessible apolar surface area accompanying complex formation. Positive \bigtriangleupCp values have not been widely reported and could typically be attributed to an increased solvent accessible apolar surface area, desolvation of polar surface area or structural transitions in the biomolecular complex. Heat shock protein-90 (Hsp90) is one of the abundant and important molecular ATP-dependent chaperones. The N-terminal domain of Hsp90 contains ATP/ADP binding site, where Hsp90-ADP interactions proceed with a large positive \bigtriangleupCp of 2.35 ± 0.46 kJ·mol-1·K-1. Interestingly geldanamycin, an Hsp90 inhibitor which binds to the same N-Hsp90-ADP/ATP binding site, interacts with a negative \bigtriangleupCp of -0.39 ± 0.04 kJ·mol-1·K-1. The semi-empirical correlation of the solvent accessible surface area change does not match well with the observed \bigtriangleupCp. This prompted us to investigate various factors affecting the thermodynamics of protein-small molecule binding including varying buffers, differing salt concentration, altering pH, substitution of different metal cations and performing interactions in heavy water. Molecular dynamics simulation and NMR studies have allowed us to disregard structural changes of N-Hsp90-ADP molecule from giving rise to positive \bigtriangleupCp. From a combination of these calorimetric, simulation and structural studies we have gathered a considerable body of evidence suggesting that the change in accessible surface area, ionic interactions and resultant desolvation of water molecules from the surface of a Mg2+ ion can contribute substantially to a positive \bigtriangleupCp. We conclude that this unique result appears to come from extensive disruption of the tightly bound water molecules present around Mg2+-ADP after binding to Hsp90, which then gives rise to a positive \bigtriangleupCp. In addition to these findings, the thermodynamics of 18 structurally related CDK2 inhibitors were investigated using ITC. CDK2 is a member of cyclin dependent kinases implicated in eukaryotic cell cycle progression and control. This investigation showed that even conservative changes in small molecule structure can reveal large variation in thermodynamic signature, while simple concepts such as van der Waals interactions, steric hindrance, and hydrophobicity are insufficient to explain it

Developing and validating Fuzzy-Border continuum solvation model with POlarizable Simulations Second order Interaction Model (POSSIM) force field for proteins

The accurate, fast and low cost computational tools are indispensable for studying the structure and dynamics of biological macromolecules in aqueous solution. The goal of this thesis is development and validation of continuum Fuzzy-Border (FB) solvation model to work with the Polarizable Simulations Second-order Interaction Model (POSSIM) force field for proteins developed by Professor G A Kaminski. The implicit FB model has advantages over the popularly used Poisson Boltzmann (PB) solvation model. The FB continuum model attenuates the noise and convergence issues commonly present in numerical treatments of the PB model by employing fixed position cubic grid to compute interactions. It also uses either second or first-order approximation for the solvent polarization which is similar to the second-order explicit polarization applied in POSSIM force field. The FB model was first developed and parameterized with nonpolarizable OPLS-AA force field for small molecules which are not only important in themselves but also building blocks of proteins and peptide side chains. The hydration parameters are fitted to reproduce the experimental or quantum mechanical hydration energies of the molecules with the overall average unsigned error of ca. 0.076kcal/mol. It was further validated by computing the absolute pKa values of 11 substituted phenols with the average unsigned error of 0.41pH units in comparison with the quantum mechanical error of 0.38pH units for this set of molecules. There was a good transferability of hydration parameters and the results were produced only with fitting of the specific atoms to the hydration energy and pKa targets. This clearly demonstrates the numerical and physical basis of the model is good enough and with proper fitting can reproduce the acidity constants for other systems as well. After the successful development of FB model with the fixed charges OPLS-AA force field, it was expanded to permit simulations with Polarizable Simulations Second-order Interaction Model (POSSIM) force field. The hydration parameters of the small molecules representing analogues of protein side chains were fitted to their solvation energies at 298.15K with an average error of ca.0.136kcal/mol. Second, the resulting parameters were used to reproduce the pKa values of the reference systems and the carboxylic (Asp7, Glu10, Glu19, Asp27 and Glu43) and basic residues (Lys13, Lys29, Lys34, His52 and Lys55) of the turkey ovomucoid third domain (OMTKY3) protein. The overall average unsigned error in the pKa values of the acid residues was found to be 0.37pH units and the basic residues was 0.38 pH units compared to 0.58pH units and 0.72 pH units calculated previously using polarizable force field (PFF) and Poisson Boltzmann formalism (PBF) continuum solvation model. These results are produced with fitting of specific atoms of the reference systems and carboxylic and basic residues of the OMTKY3 protein. Since FB model has produced improved pKa shifts of carboxylic residues and basic protein residues in OMTKY3 protein compared to PBF/PFF, it suggests the methodology of first-order FB continuum solvation model works well in such calculations. In this study the importance of explicit treatment of the electrostatic polarization in calculating pKa of both acid and basic protein residues is also emphasized. Moreover, the presented results demonstrate not only the consistently good degree of accuracy of protein pKa calculations with the second-degree POSSIM approximation of the polarizable calculations and the first-order approximation used in the Fuzzy-Border model for the continuum solvation energy, but also a high degree of transferability of both the POSSIM and continuum solvent Fuzzy Border parameters. Therefore, the FB model of solvation combined with the POSSIM force field can be successfully applied to study the protein and protein-ligand systems in water