Fragment molecular orbital calculations for biomolecules

Exploring biomolecule behavior, such as proteins and nucleic acids, using quantum mechanical theory can identify many life science phenomena from first principles. Fragment molecular orbital (FMO) calculations of whole single particles of biomolecules can determine the electronic state of the interior and surface of molecules and explore molecular recognition mechanisms based on intermolecular and intramolecular interactions. In this review, we summarized the current state of FMO calculations in drug discovery, virology, and structural biology, as well as recent developments from data science.     

Kinetic, energetic, and stereochemical factors determining the molecular recognition of proteins and nucleic acids

In the context of stereochemical modeling, it has been shown that damage to the hydration shell of proteins and nucleic acids should be confronted by considerable kinetic barriers caused by the breakage of hydrogen bonds of the shell. Since the structure of the hydration shell is determined by the surface of proteins and nucleic acids, the kinetic barriers arising during the breakage of the shell differ greatly in different regions of the biopolymer surface. In turn, this means that the probability of the participation of different surface regions of proteins and nucleic acids in intermolecular interactions should vary within a wide range; i.e., hydration shells should enhance the selectivity of molecular recognition.     

The structural stability and catalytic activity of DNA and RNA oligonucleotides in the presence of organic solvents

Organic solvents and apolar media are used in the studies of nucleic acids to modify the conformation and function of nucleic acids, to improve solubility of hydrophobic ligands, to construct molecular scaffolds for organic synthesis, and to study molecular crowding effects. Understanding how organic solvents affect nucleic acid interactions and identifying the factors that dominate solvent effects are important for the creation of oligonucleotide-based technologies. This review describes the structural and catalytic properties of DNA and RNA oligonucleotides in organic solutions and in aqueous solutions with organic cosolvents. There are several possible mechanisms underlying the effects of organic solvents on nucleic acid interactions. The reported results emphasize the significance of the osmotic pressure effect and the dielectric constant effect in addition to specific interactions with nucleic acid strands. This review will serve as a guide for the selection of solvent systems based on the purpose of the nucleic acid-based experiments.     

Anion binding to nucleic acids

Nucleic acids are generally considered as efficient cation binders. Therefore, the likelihood that negatively charged ions might intrude their first hydration shell is rarely considered. Here, we show on the basis of (i) a survey of the Nucleic Acid Database, (ii) several structures extracted from the Cambridge Structural Database, and (iii) molecular dynamics simulations, that the nucleotide electropositive edges involving mainly amino, imino, and hydroxyl groups can cast specific anion binding sites. These binding sites constitute also good locations for the binding of the negatively charged groups of the Asp and Glu residues or the nucleic acid phosphate groups. Furthermore, it is observed in several instances that anions, like water molecules and cations, do mediate protein/nucleic acid interactions. Thus, anions as well as negatively charged groups are directly involved in specific recognition and folding phenomena involving polyanionic nucleic acids.     

Viscosity B-coefficients and standard partial molar volumes of amino acids, and their roles in interpreting the protein (enzyme) stabilization

This review systematically surveys the viscosity B-coefficients and standard partial molar volumes of amino acids at various temperatures as these data are quite important for interpreting the hydration and other properties of peptides and proteins. The effect of organic solutes and various ions on the viscometric and volumetric properties of amino acids has also been discussed in terms of their kosmotropic ('structure-making') effects on the hydration of amino acids. The comparison of these effects on the amino acid hydration enables us to have a better understanding of the influence of organic solute and salt on the protein stabilization. In addition, the viscometric and volumetric behaviors of amino acid ions (cations and anions) are also summarized because these ions have recently been incorporated as part of novel ionic liquids, which have wide applications in biocatalysis and protein stabilization.     

Crystallographic Studies of Chemically Modified Nucleic Acids: A Backward Glance

Chemically modified nucleic acids (CNAs) are widely explored as antisense oligonucleotide or small interfering RNA (siRNA) candidates for therapeutic applications. CNAs are also of interest in diagnostics, high‐throughput genomics and target validation, nanotechnology and as model systems in investigations directed at a better understanding of the etiology of nucleic acid structure, as well as the physicochemical and pairing properties of DNA and RNA, and for probing protein–nucleic acid interactions. In this article, we review research conducted in our laboratory over the past two decades with a focus on crystal‐structure analyses of CNAs and artificial pairing systems. We highlight key insights into issues ranging from conformational distortions as a consequence of modification to the modulation of pairing strength, and RNA affinity by stereoelectronic effects and hydration. Although crystal structures have only been determined for a subset of the large number of modifications that were synthesized and analyzed in the oligonucleotide context to date, they have yielded guiding principles for the design of new analogs with tailor‐made properties, including pairing specificity, nuclease resistance, and cellular uptake. And, perhaps less obviously, crystallographic studies of CNAs and synthetic pairing systems have shed light on fundamental aspects of DNA and RNA structure and function that would not have been disclosed by investigations solely focused on the natural nucleic acids.     

Kinetic, energetic and stereochemical factors determining molecular recognition of proteins and nucleic acids

It is shown within the framework of stereochemical modeling that disruption of water shells of proteins and nucleic acids is confronted by significant kinetic barriers caused by the breaking of hydrogen bonds. The structure of the water shells is dictated by the surface of proteins and nucleic acids, therefore the kinetic barriers due to disruption of the water shell are strongly distinct from each other on different parts of the shell. This, in turn, means that the probability of participation of different parts of the protein and nucleic acid surfaces in intermolecular interactions should be varied through a wide range, i.e. the water shell should strengthen selectivity of molecular recognition.     

"Phantom" structure of solvents and packing of dual-chain nucleic acid molecules in liquid crystal dispersion particles

The properties of mesomorphic dispersions of double-stranded nucleic acids were studied. A comparison of these properties indicates that their diversity cannot be explained unambiguously in terms of the conception of Van-der-Waals interactions in particles of mesomorphic dispersions without regard for the specific properties of the solvent, water, in the vicinity of adjacent nucleic acid molecules. It was assumed that, with small distances between the molecules of nucleic acids, a specific "phantom" structure of the solvent appears in their vicinity, which acts as an elastic medium that modifies the interactions between nucleic acid molecules and as a medium in which a collective tunneling of protons can occur. The combination of the two effects determines the "recognition" of nucliec acid molecules and the stabilization of the cholesteric structure of mesomorphic dispersions of nucleic acids.     

Hydration of proteins and nucleic acids: Advances in experiment and theory. A review

BackgroundMost biological processes involve water, and the interactions of biomolecules with water affect their structure, function and dynamics.Scope of reviewThis review summarizes the current knowledge of protein and nucleic acid interactions with water, with a special focus on the biomolecular hydration layer. Recent developments in both experimental and computational methods that can be applied to the study of hydration structure and dynamics are reviewed, including software tools for the prediction and characterization of hydration layer properties.Major conclusionsIn the last decade, important advances have been made in our understanding of the factors that determine how biomolecules and their aqueous environment influence each other. Both experimental and computational methods contributed to the gradually emerging consensus picture of biomolecular hydration.General significanceAn improved knowledge of the structural and thermodynamic properties of the hydration layer will enable a detailed understanding of the various biological processes in which it is involved, with implications for a wide range of applications, including protein-structure prediction and structure-based drug design.     

Thermodynamic database for protein-nucleic acid interactions (ProNIT).

MOTIVATION: Protein-nucleic acid interactions are fundamental to the regulation of gene expression. In order to elucidate the molecular mechanism of protein-nucleic acid recognition and analyze the gene regulation network, not only structural data but also quantitative binding data are necessary. Although there are structural databases for proteins and nucleic acids, there exists no database for their experimental binding data. Thus, we have developed a Thermodynamic Database for Protein-Nucleic Acid Interactions (ProNIT). RESULTS: We have collected experimentally observed binding data from the literature. ProNIT contains several important thermodynamic data for protein-nucleic acid binding, such as dissociation constant (K(d)), association constant (K(a)), Gibbs free energy change (DeltaG), enthalpy change (DeltaH), heat capacity change (DeltaC(p)), experimental conditions, structural information of proteins, nucleic acids and the complex, and literature information. These data are integrated into a relational database system together with structural and functional information to provide flexible searching facilities by using combinations of various terms and parameters. A www interface allows users to search for data based on various conditions, with different display and sorting options, and to visualize molecular structures and their interactions. AVAILABILITY: ProNIT is freely accessible at the URL http://www.rtc.riken.go.jp/jouhou/pronit/pronit.html.     

How large are the volume changes accompanying protein transitions and binding?

We present a simple model to describe volume changes accompanying protein folding and binding events. The model enables one to resolve the changes in volume accompanying conformational transitions of proteins as well as association of proteins with other molecules in terms of the intrinsic, thermal and interaction (hydration) contributions. The thermal contribution to protein volume results from thermally activated mutual vibrational motions of contacting solute and solvent molecules. Our calculations suggest that near zero volume changes accompanying protein folding and binding events reflect compensation between significant changes in the intrinsic, thermal and interaction terms. We have quantitatively estimated these terms as a function of the protein's molecular weight and degree of its unfolding. Results described in this work lay foundation for more reliable and physically justified interpretations of volumetric data on protein folding and binding events. We also discuss potential ways of extending applications of our model to analyzing other macromolecular systems and events, including drug-DNA and protein-DNA interactions and helix-to-helix and helix-to-coil transitions of nucleic acids.     

DNA polymorphism: a comparison of force fields for nucleic acids

The improvements of the force fields and the more accurate treatment of long-range interactions are providing more reliable molecular dynamics simulations of nucleic acids. The abilities of certain nucleic acid force fields to represent the structural and conformational properties of nucleic acids in solution are compared. The force fields are AMBER 4.1, BMS, CHARMM22, and CHARMM27; the comparison of the latter two is the primary focus of this paper. The performance of each force field is evaluated first on its ability to reproduce the B-DNA decamer d(CGATTAATCG)(2) in solution with simulations in which the long-range electrostatics were treated by the particle mesh Ewald method; the crystal structure determined by Quintana et al. (1992) is used as the starting point for all simulations. A detailed analysis of the structural and solvation properties shows how well the different force fields can reproduce sequence-specific features. The results are compared with data from experimental and previous theoretical studies.     

The interactions of nucleic acids at elevated hydrostatic pressure

The application of elevated hydrostatic pressure on the order of a few thousand bar provides insight into the molecular forces responsible for stabilizing the conformations and non-covalent interactions of biological molecules in aqueous solution. In particular, the parameters derived from these studies have enabled researchers to glean information regarding the importance of hydration in the energetics and kinetics of these systems. This review presents data concerned with the application of hydrostatic pressure to study the thermodynamics, kinetics, and structure of nucleic acids and the interactions between nucleic acids and proteins, enzymes, and drugs. These complexes often form extremely stable non-covalent complexes in which electrostatic interactions play an important role. The sensitivity of these interactions to pressure offers a valuable experimental tool for investigating the energetics of the complexes.     

Volumetric characterization of the hydration properties of heterocyclic bases and nucleosides

We have determined the partial molar volumes, expansibilities, and adiabatic compressibilities of six heterocyclic nucleic acid bases, five ribonucleosides, and six 2'-deoxyribonucleosides within the temperature range 18-55 degrees C. We interpret the resulting data in terms of the hydration of the component hydrophobic and polar atomic groups. From our temperature-dependent volumetric studies, we found that the total contraction of water caused by polar groups of each individual heterocyclic base and nucleoside depends on the proximity and chemical nature of other functional groups of the solute. In addition, the compressibility contributions of polar groups vary greatly in sign and magnitude depending on the surrounding functional groups. In agreement with previous studies, our results are suggestive of little or no interaction between the sugar and base moieties of a nucleoside. In general, our data shed light into the hydration properties of individual heterocyclic bases and nucleosides, which may have significant implications for the sequence-dependent hydration of nucleic acids. We discuss the potential importance of our results for developing an understanding of the role that solvent plays in the stabilization/destabilization of nucleic acid structures.     

Modeling nucleic acids

Nucleic acids are an important class of biological macromolecules that carry out a variety of cellular roles. For many functions, naturally occurring DNA and RNA molecules need to fold into precise three-dimensional structures. Due to their self-assembling characteristics, nucleic acids have also been widely studied in the field of nanotechnology, and a diverse range of intricate three-dimensional nanostructures have been designed and synthesized. Different physical terms such as base-pairing and stacking interactions, tertiary contacts, electrostatic interactions and entropy all affect nucleic acid folding and structure. Here we review general computational approaches developed to model nucleic acid systems. We focus on four key areas of nucleic acid modeling: molecular representation, potential energy function, degrees of freedom and sampling algorithm. Appropriate choices in each of these key areas in nucleic acid modeling can effectively combine to aid interpretation of experimental data and facilitate prediction of nucleic acid structure.     

Structural aspects of nucleic acid-sensing Toll-like receptors

Invading pathogens elicit potent immune responses in cells through interactions between structurally conserved molecules derived from the pathogens and specialized innate immune receptors such as the Toll-like receptors (TLRs). Nucleic acid is one of the principal TLR ligands. Nucleic acid-sensing TLRs recognize an array of nucleic acids, including double-stranded RNA, single-stranded RNA, and DNAs with specific sequence motifs. Although ligand-induced dimerization is commonly observed followed by TLR activation, both the specific recognition mechanisms and the ligand–receptor interactions vary among different TLRs. In this review, we highlight our current understanding of how these receptors recognize their cognate ligands based on the recent advances in structural biology.     

The hydration of nucleic acid duplexes as assessed by a combination of volumetric and structural techniques

Using high precision densimetric and ultrasonic measurements, we have determined, at 25°C, the apparent molar volumes ΦV and the apparent molar compressibilities ΦK_S of four nucleic acid duplexes—namely, the DNA duplex, poly(dIdC)poly(dIdC); the RNA duplex, poly(rA)poly(rU); and the two DNA/RNA hybrid duplexes, poly(rA)poly(dT) and poly(dA)poly(rU). Using available fiber diffraction data on these duplexes, we have calculated the molecular volumes as well as the solvent‐accessible surface areas of the constituent charged, polar, and nonpolar atomic groups. We found that the hydration properties of these nucleic acid duplexes do not correlate with the extent and the chemical nature of the solvent‐exposed surfaces, thereby suggesting a more specific set of duplex–water interactions beyond general solvation effects. A comparative analysis of our volumetric data on the four duplexes, in conjunction with available structural information, suggests the following features of duplex hydration: (a) The four duplexes exhibit different degrees of hydration, in the order poly(dIdC)poly(dIdC) > poly(dGdC)poly(dGdC) > poly(dAdT)poly(dAdT) ≈ poly(dA)poly(dT). (b) Repetitive AT and IC sequences within a duplex are solvated beyond general effects by a spine of hydration in the minor groove, with this sequence‐specific water network involving about 8 additional water molecules from the second and, perhaps, even the third hydration layers. (c) Repetitive GC and IC sequences within a duplex are solvated beyond general effects by a “patch of hydration” in the major groove, with this water network involving about 13 additional water molecules from the second and, perhaps, even the third hydration layers. (d) Random sequence, polymeric DNA duplexes, which statistically lack extended regions of repetitive AT, GC, or IC sequences, do not experience such specific enhancements of hydration. Consequently, consistent with our previous observations (T. V. Chalikian, A. P. Sarvazyan, G. E. Plum, and K. J. Breslauer, Biochemistry, 1994, Vol. 33, pp. 2394–2401), duplexes with approximately 50% AT content exhibit the weakest hydration, while an increase or decrease from this AT content causes enhancement of hydration, either due to stronger hydration of the minor groove (an increase in AT content) or due to stronger hydration of the major groove (an increase in GC content). (e) In dilute aqueous solutions, a B‐DNA duplex is more hydrated than an A‐DNA duplex, a volumetric‐based conclusion that is in agreement with previous results obtained on crystals, fibers, and DNA solutions in organic solvent–water mixtures. (f) the A‐like, RNA duplex poly(rA)poly(rU) and the structurally similar A‐like, hybrid duplex poly(rA)poly(dT), exhibit similar hydration properties, while the structurally distinct A‐like, hybrid duplex poly(rA)poly(dT) and non‐A‐like, hybrid duplex poly(dA)poly(rU) exhibit differential hydration properties, consistent with structural features dictating hydration characteristics. We discuss how volumetric characterizations, in conjunction with structural studies, can be used to describe, define, and resolve the general and sequence/conformation‐specific hydration properties of nucleic acid duplexes. © 1999 John Wiley & Sons, Inc. Biopoly 50: 459–471, 1999     

Thermodynamic database supports deciphering protein–nucleic acid interactions

The thermodynamics of protein–nucleic acid interactions (PNIs) is crucial for elucidating the mechanisms of molecular recognition and pathological consequences. The Protein–Nucleic Acid Thermodynamics Database (PNATDB) is a database containing experimentally determined thermodynamic parameters along with sequence, structural, and function data, which is available free online.     

Thermodynamics of drug-DNA interactions

Many anticancer, antibiotic, and antiviral drugs exert their primary biological effects by reversibly interacting with nucleic acids. Therefore, these biomolecules represent a major target in drug development strategies designed to produce next generation therapeutics for diseases such as cancer. In order to improve the clinical efficacy of existing drugs and also to design new ones it is necessary to understand the molecular basis of drug-DNA interactions in structural, thermodynamic, and kinetic detail. The past decade has witnessed an increase in the number of rigorous biophysical studies of drug-DNA systems and considerable knowledge has been gained in the energetics of these binding reactions. This is, in part, due to the increased availability of high-sensitivity calorimetric techniques, which have allowed the thermodynamics of drug-DNA interactions to be probed directly and accurately. The focus of this article is to review thermodynamic approaches to examining drug-DNA recognition. Specifically, an overview of a recently developed method of analysis that dissects the binding free energy of these reactions into five component terms is presented. The results of applying this analysis to the DNA binding interactions of both minor groove drugs and intercalators are discussed. The solvent water plays a key role in nucleic acid structure and consequently in the binding of ligands to these biomolecules. Any rational approach to DNA-targeted drug design requires an understanding of how water participates in recognition and binding events. Recent studies examining hydration changes that accompany DNA binding by intercalators will be reviewed. Finally some aspects of cooperativity in drug-DNA interactions are described and the importance of considering cooperative effects when examining these reactions is highlighted.