Steven J. Wilkens

Bio: Steven J. Wilkens is an academic researcher from University of Wisconsin-Madison. The author has contributed to research in topics: Rubredoxin & Fermi contact interaction. The author has an hindex of 9, co-authored 9 publications receiving 604 citations. Previous affiliations of Steven J. Wilkens include University of Pennsylvania.

Collagen stability: insights from NMR spectroscopic and hybrid density functional computational investigations of the effect of electronegative substituents on prolyl ring conformations

Abstract: Collagen-like peptides of the type (Pro-Pro-Gly)10 fold into stable triple helices. An electron-withdrawing substituent at the Hγ3 ring position of the second proline residue stabilizes these triple helices. The aim of this study was to reveal the structural and energetic origins of this effect. The approach was to obtain experimental NMR data on model systems and to use these results to validate computational chemical analyses of these systems. The most striking effects of an electron-withdrawing substituent are on the ring pucker of the substituted proline (Proi) and on the trans/cis ratio of the Xaai-1−Proi peptide bond. NMR experiments demonstrated that N-acetylproline methyl ester (AcProOMe) exists in both the Cγ-endo and Cγ-exo conformations (with the endo conformation slightly preferred), N-acetyl-4(R)-fluoroproline methyl ester (Ac-4R-FlpOMe) exists almost exclusively in the Cγ-exo conformation, and N-acetyl-4(S)-fluoroproline methyl ester (Ac-4S-FlpOMe) exists almost exclusively in the Cγ-endo co...

Natural J-Coupling Analysis: Interpretation of Scalar J-Couplings in Terms of Natural Bond Orbitals

Abstract: The natural J-coupling (NJC) method presented here analyzes the Fermi contact portion of J-coupling in the framework of finite perturbation theory applied to ab initio/density function theory (DFT) wave functions, to compute individual and pairwise orbital contributions to the net J-coupling. The approach is based on the concepts and formalisms of natural bond orbital (NBO) methods. Computed coupling contributions can be classified as Lewis (individual orbital contributions corresponding to the natural Lewis structure of the molecule), delocalization (resulting from pairwise donor−acceptor interactions), and residual repolarization (corresponding to correlation-like interactions). This approach is illustrated by an analysis of the angular and distance dependences of the contributions to vicinal 3JHH couplings in ethane and to the long-range 6JHH couplings in pentane. The results indicate that approximately 70% or more of the net J-coupling is propagated by steric exchange antisymmetry interactions between...

NMR Investigations of Clostridium pasteurianum Rubredoxin. Origin of Hyperfine 1H, 2H, 13C, and 15N NMR Chemical Shifts in Iron−Sulfur Proteins As Determined by Comparison of Experimental Data with Hybrid Density Functional Calculations†

Abstract: High-level, all-electron, density functional calculations on a 104-atom model (B3LYP/6-311G** level) have been used, in conjunction with high-resolution X-ray structural data, to predict the remarkable paramagnetic contact shifts recently measured for 1H, 2H, 13C, and 15N nuclei in Clostridium pasteurianum rubredoxin. Three published X-ray structures for the Fe(III) rubredoxin from C. pasteurianum were employed to construct a 104-atom model for the iron center that included all atoms shown to have strong electronic interactions with the Fe. Each of these models served as a starting point for quantum mechanical calculations at level B3LYP/6-311G**, which, in turn, yielded calculated values for Fermi contact spin densities. The results indicate that the experimental hyperfine shifts are dominated by Fermi contact interactions: calculated Fermi contact spin densities were found to correlate linearly with isotropic hyperfine 1H, 2H, 13C, and 15N NMR chemical shifts determined for Fe(III) rubredoxin. At the c...

Trans-Hydrogen-Bond h2JNN and h1JNH Couplings in the DNA A−T Base Pair: Natural Bond Orbital Analysis

Abstract: Natural bond orbital (NBO) analysis described here demonstrates that trans-hydrogen-bond (trans-H-bond) NMR J couplings in the DNA A-T base pair, h2JNN and h1JNH, are determined largely by three terms: two Lewis-type contributions (the single-orbital contribution from the adenine lone pair and the contribution from the sigmaN3H3 natural bond orbital of the thymine ring) and one contribution from pairwise delocalization of spin density (between the lone pair in adenine and the sigma* antibonding orbital linking N3 and H3 of thymine). For h2JNN coupling, all three contributions are positive, whereas for h1JNH coupling, the delocalization term is negative, and the other two terms are positive, resulting in a small net positive coupling constant. This result rationalizes the experimental findings that the two-bond coupling (h2JNN approximately 9 Hz) is larger than the one-bond coupling (h1JNH approximately 3 Hz) and demonstrates that the same hyperconjugative and steric mechanisms that stabilize the H-bond are involved in the transmission of J coupling information. The N1...H3-N3 H-bond of the DNA A-T base pair is found to exhibit significant covalent character, but steric effects contribute almost equally to the trans-H-bond coupling.

Redox-Dependent Magnetic Alignment of Clostridium pasteurianum Rubredoxin: Measurement of Magnetic Susceptibility Anisotropy and Prediction of Pseudocontact Shift Contributions

Abstract: An analysis of the magnetic field dependence of one-bond couplings has yielded the magnetic susceptibility anisotropies for Clostridium pasteurianum rubredoxin (Rdx) in its oxidized Fe(III) and reduced Fe(II) states. Experimental one-bond 1HN−15N and 1Hα−13Cα couplings were measured at two field strengths (corresponding to 400 and 750 MHz 1H frequencies) and decomposed into their field-independent scalar (1J) and field-dependent dipolar (1D) components. The total numbers of measured dipolar couplings (1HN−15N plus 1Hα−13Cα) were 50 for oxidized Rdx and 49 for reduced Rdx. The atom pairs giving rise to these signals are located >11 A from the iron; those closer to the iron are too broad to be resolved in two-dimensional NMR spectra and may exhibit large Fermi contact shifts. A five-dimensional grid search and Powell minimization of the difference between each set of measured dipolar couplings and those calculated from an X-ray crystal structure of Fe(III) Rdx yielded the magnitude and orientation of the ma...

Collagen Structure and Stability

Abstract: Collagen is the most abundant protein in animals. This fibrous, structural protein comprises a right-handed bundle of three parallel, left-handed polyproline II-type helices. Much progress has been made in elucidating the structure of collagen triple helices and the physicochemical basis for their stability. New evidence demonstrates that stereoelectronic effects and preorganization play a key role in that stability. The fibrillar structure of type I collagen—the prototypical collagen fibril—has been revealed in detail. Artificial collagen fibrils that display some properties of natural collagen fibrils are now accessible using chemical synthesis and self-assembly. A rapidly emerging understanding of the mechanical and structural properties of native collagen fibrils will guide further development of artificial collagenous materials for biomedicine and nanotechnology.

Applications of Fluorine in Medicinal Chemistry

Abstract: The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, 18F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in po...

Fluorine in medicinal chemistry and chemical biology

Abstract: Introduction Chapter 1 "Unique Properties of Fluorine and Their Relevance to Medicinal Chemistry and Chemical Biology" by Takashi Yamazaki, Takeo Taguchi and Iwao Ojima Medicinal Chemistry Chapter 2 "Fluorinated Prostanoids: Development of Tafluprost, a New Anti-glaucoma Agent" by Yasushi Matsumura Chapter 3 "Fluorinated conformationally restricted glutamate analogs for CNS drug discovery and development" by Atsuro Nakazato Chapter 4 "Fluorinated Inhibitors of Matrix Metalloproteinases" by Roberta Sinisi, Monika Jagodzinska, Gabriele Candiani, Florent Huguenot, Monica Sani, Alessandro Volonterio, Raffaella Maffezzoni and Matteo Zanda Chapter 5 "Fluoro-Taxoid Anticancer Agents" by Antonella Pepe, Larisa Kuznetsova, Liang Sun and Iwao Ojima Chapter 6 "Antimalarial Fluoroartemisinins: Increased Metabolic and Chemical Stability"by Jean-Pierre Begue, Daniele Bonnet-Delpon Chapter 7 "Synthesis and Biological Activity of Fluorinated Nucleosides" by Tokumi Maruyama, Masahiro Ikejiri, Kunisuke Izawa and Tomoyuki Onishi Synthetic methods for medicinal chemistry and chemical biology Chapter 8 "Synthesis of gem -Difluoromethylenated Nucleosides via gem -Difluoromethylene-Containing Building Blocks" by Wei-Dong Meng and Feng-Ling Qing Chapter 9 "Recent Advances in the Syntheses of Fluorinated Amino Acids" by Kenji Uneyama Chapter 10 "Fluorinated Moieties for Replacement of Amide and Peptide Bonds" by Takeo Taguchi and Hikaru Yanai Chapter 11 "Perfluorinated Heteroaromatic Systems as Scaffolds for Drug Discovery" by David Armstrong, Matthew W. Cartwright, Emma L. Parks, Graham Pattison, Graham Sandford, Rachel Slater, John A. Christopher, David D. Miller, Paul W. Smith and Antonio Vong Chapter 12 " gem -Difluorocyclopropanes as key building blocks for novel biologically active molecules" by Toshiyuki Itoh Chapter 13 "Fluorous Mixture Synthesis (FMS) of Drug-Like Molecules and Enantiomers, Stereoisomers, and Analogs of Natural Products" by Wei Zhang Chapter 14 "Fluorine-18 Radiopharmaceuticals" by Michael R. Kilbourn and Xia Shao Applications of fluorinated amino acids and peptides to chemical biology and pharmacology Chapter 15 "Application of Artificial Model Systems to Study the Interactions of Fluorinated Amino Acids within the Native Environment of Coiled Coil Proteins" by Mario Salwiczek, Toni Vagt and Beate Koksch Chapter 16 "Fluorinated Amino Acids and Biomolecules in Protein Design and Chemical Biology" by He Meng, Ginevra A. Clark , and Krishna Kumar Chapter 17 "Effects of Fluorination on the Bioorganic Properties of Methionine" by John F. Honek Chapter 18 "Structure analysis of membrane-active peptides using 19 F-labeled amino acids and solid state NMR" by Parvesh Wadhwani and Erik Strandberg Chapter 19 "Metabolism of Fluorine-containing Drugs using in vivo Magnetic Resonance Spectroscopy" by Erika Schneider Appendix "FDA-Approved Active Pharmaceutical Ingredients Containing Fluorine" by Elizabeth Pollina-Cormier, Manisha Das, and Iwao Ojima

Natural bond orbital methods

Abstract: Natural bond orbital (NBO) methods encompass a suite of algorithms that enable fundamental bonding concepts to be extracted from Hartree-Fock (HF), Density Functional Theory (DFT), and post-HF computations. NBO terminology and general mathematical formulations for atoms and polyatomic species are presented. NBO analyses of selected molecules that span the periodic table illustrate the deciphering of the molecular wavefunction in terms commonly understood by chemists: Lewis structures, charge, bond order, bond type, hybridization, resonance, donor–acceptor interactions, etc. Upcoming features in the NBO program address ongoing advances in ab initio computing technology and burgeoning demands of its user community by introducing major new methods, keywords, and electronic structure system/NBO communication enhancements. © 2011 John Wiley & Sons, Ltd.

Metalloproteins containing cytochrome, iron-sulfur, or copper redox centers.

Abstract: Redox reactions play important roles in almost all biological processes, including photosynthesis and respiration, which are two essential energy processes that sustain all life on earth. It is thus not surprising that biology employs redox-active metal ions in these processes. It is largely the redox activity that makes metal ions uniquely qualified as biological cofactors and makes bioinorganic enzymology both fun to explore and challenging to study. Even though most metal ions are redox active, biology employs a surprisingly limited number of them for electron transfer (ET) processes. Prominent members of redox centers involved in ET processes include cytochromes, iron–sulfur clusters, and cupredoxins. Together these centers cover the whole range of reduction potentials in biology (Figure ​(Figure1).1). Because of their importance, general reviews about redox centers1−77 and specific reviews about cytochromes,8,24,78−90 iron–sulfur proteins,91−93 and cupredoxins94−104 have appeared in the literature. In this review, we provide both classification and description of each member of the above redox centers, including both native and designed proteins, as well as those proteins that contain a combination of these redox centers. Through this review, we examine structural features responsible for their redox properties, including knowledge gained from recent progress in fine-tuning the redox centers. Computational studies such as DFT calculations become more and more important in understanding the structure–function relationship and facilitating the fine-tuning of the ET properties and reduction potentials of metallocofactors in proteins. Since this aspect has been reviewed extensively before,105−110 and by other reviews in this thematic issue,2000,2001,2002 it will not be covered here. Open in a separate window Figure 1 Reduction potential range of redox centers in electron transfer processes.