Chemistry
Conformational Analysis
Conformational analysis involves studying the different spatial arrangements of atoms in a molecule due to rotation around single bonds. It explores the energy differences and stabilities of these conformations, providing insights into the structure and behavior of molecules. This analysis is crucial for understanding the reactivity, biological activity, and physical properties of organic compounds.
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10 Key excerpts on "Conformational Analysis"
eBook - PDF- Philip J. Stephens, Frank J. Devlin, James R. Cheeseman(Authors)
- 2012(Publication Date)
- CRC Press(Publisher)
81 5 Conformational Analysis The objectives of the Conformational Analysis of a molecule are to determine the num-ber of minima on the potential energy surface (PES) of the molecule, i.e., the number of stable conformations, and the geometries and energies of each stable conforma-tion. The number, geometries, and energies of the stable conformations of a molecule depend on the methodology used to calculate the PES. Ideally, when infrared (IR) and vibrational circular dichroism (VCD) spectra are to be calculated using density func-tional theory (DFT), Conformational Analysis should also be carried out using DFT. For very small molecules this is straightforward. For example, consider the chiral substituted oxiranes, methyl-oxirane, 1 , and phenyl-oxirane, 2 . O C O H 3 H 1 H 2 1 2 3 1 2 3 4 S -1 S -2 H H H H H H The oxirane ring is conformationally rigid, as are also the methyl and phenyl sub-stituents. However, in 1 the methyl group can rotate about the C–C bond, connecting it to the oxirane ring, and in 2 , the phenyl group can rotate about the C–C bond, connecting it to the oxirane ring. To determine the number of stable conformations of 1 and 2 , relaxed scans of their PESs with respect to rotation of the CH 3 and C 6 H 5 groups are carried out. Specifically, the dihedral angles C 1 C 2 C 3 H 1 of 1 and C 1 C 2 C 3 C 4 of 2 are varied from 0 to 360°. For each value of the dihedral angle, optimization of the molecule is carried out, giving the relaxed energy. The plot of the relaxed ener-gies vs. the dihedral angle values is the relaxed PES scan. The relaxed PES scan of S -1 calculated at the B3LYP/6-31G* level with C 1 C 2 C 3 H 1 being varied in steps of 10° is shown in Figure 5.1. Three valleys in the PES are observed, and therefore, three stable conformations are predicted. In Table 5.1, C 1 C 2 C 3 H 1 dihedral angles and the relative energies of the lowest-energy structures are listed.
- Patrick Bultinck, Hans De Winter, Wilfried Langenaeker, Jan P. Tollenare, Patrick Bultinck, Hans De Winter, Wilfried Langenaeker, Jan P. Tollenare(Authors)
- 2003(Publication Date)
- CRC Press(Publisher)
But in many cases, the biological target is not yet known or structurally not determined. Studies by superimposing sets of highly active compounds can provide a more detailed insight into the structural and electronic situation at the binding site of the receptor, if conformational degrees of freedom are allowed for the molecules during the superimposition procedure [5,6]. In addition, methods such as pharmaco- phore searches in 3D databases perform much more efficiently with higher hit rates Sadowski et al. 152 and larger numbers of potential new drugs or lead structures if the molecules in the database are considered to be conformationally flexible [7]. Furthermore, even if the biological receptor is known and structurally deter- mined, modern techniques such as virtual screening and docking experiments or de novo design systems have to take into account several alternative conformations of the small molecules under investigation to estimate and rank different binding modes and constants with locally optimized electrostatic and steric interactions between the ligand and its receptor [8]. Clearly, there is a need for computational tools that generate ensembles of con- formations and a substantial step toward the understanding of the physical, chemical or biological, and pharmacological properties of a molecule to study or to analyze its possible conformations. Conformational Analysis tries to correlate conformational changes of a molecule with the influence on its properties. The major aim of Conformational Analysis is to identify the preferred confor- mations of a molecule under specific conditions. Therefore, conformational search techniques (i.e., methods that locate the global and local energy minima of a structure) play a crucial role in Conformational Analysis. In the context of computer-aided drug discovery and design, the optimal search method would seek for and identify one single conformation, the biologically active one.
eBook - PDF- A Kitaigorodsky(Author)
- 2012(Publication Date)
- Academic Press(Publisher)
Chapter VII Conformations of Organic Molecules 1. THE MECHANICAL MODEL OF A MOLECULE In the preceding chapters the problems pertaining to the mutual positions of the molecules in a crystal have been discussed. This chapter deals with the mutual positions of the atoms in a molecule, i.e., the conformation of the molecule. Conformational concepts have become one of the most important fields of organic chemistry. The properties of the molecule, e.g., reactivity, reaction rate, bond strength, the heats of formation and hydrogénation of unsaturated compounds, etc., are ascribed by chemists to the molecular geometry. Thus they disguise the relationship between geometry and properties of the molecule by the somewhat indefinite term steric effects. Nowadays the theory of Conformational Analysis makes possible quantitative evaluation of these steric effects. If a molecule is looked upon as a system of electrons and nuclei, then, by solving the Schrödinger equation in every case, we may derive all the properties of the molecule, including its geometry. But, nonempirical calculations involve extremely complicated, sometimes insurmountable, mathematical difficulties ; hence the attempts to find more expedient—empirical—solutions. The success-ful application of atom-atom potentials to the estimation of intermolecular forces gives us grounds to believe that this approach will be no less fruitful in the case of the interatomic potentials within molecules. 381 382 7 Conformations of Organic Molecules The concept of the theoretical Conformational Analysis of organic molecules was put forward as early as late forties and early fifties independently by Hill [1,1a], Westheimer [2-6] and Kitaigorodsky [6-8]. These early contributions are analyzed in [9, 10]. The mechanical model underlying theoretical con-formation analysis is based on the Born-Oppenheimer approximation.
eBook - PDFStereochemistry
Basic Concepts and Applications
- M. Nógrádi(Author)
- 2013(Publication Date)
- Pergamon(Publisher)
Different conformers of a given compound can arise from stereoisomers through rotation around single bonds. It should be recalled that configuration and conformation are complementary concepts; configuration is a qualitative and conformation a quantitative term. A compound of a given configuration may assume many conformations each characterized by different sets of dihedral angles. Conformations, in turn, may be aehiral or chiral, and to the latter configurational symbols may be assigned. Energy relationships may be excluded from the discussionof configuration, whereas with conformation this is impossible. If this were not so, geometrical isomers which arise from rotation around double bonds, a process which involves considerable energy, would have to be classified as conformers. As stated above, conformations can be described in terms of torsion angles, and certain stable conformations are usually referred to as conformers. Special names are assigned to some conformers. One of the objects of Conformational Analysis is to select from the infinite number of possible conformations for a given compound those which are 93 relatively stable. In order that we may assess the conformational behaviour of complex molecules, some simple molecules such as ethane, n-butane, and cyclohexane will first be analyzed. 1.2.1 The conformation of ethane. Torsional strain When two non-bonding atoms approach each other a weak attraction is first set up between them, but once the distance is less than that correspond-ing to the sum of the van der Waals' radii the atoms experience a sharply increasing repulsion (cf. Fig. 1). For this reason the closest distance of ap-proach between non-bonding atoms is the sum of their van der Waals' radii.
- Roger L. Lundblad(Author)
- 2009(Publication Date)
- Chapman and Hall/CRC(Publisher)
There is somewhat less interest in the use of Conformational Analysis. There are several reasons for this. First, to a certain extent, conformational analyses for purposes of identity or comparability only are useful if there is no change: if there is change, it is usually, but not always, difficult to quantitate as compared, for example, to a chemical modification in the peptide chain. However, there are a variety of techniques that can be used to study protein conformation. 54 Analytical techniques such as amino acid analysis and mass spectrometry pro-vide information regarding the chemical structure of the product. Techniques such as electrophoresis, chromatography, and size exclusion chromatography provide infor-mation about purity and can, in selected situations, provide insight into conformation and chemical structure. Hydrophobic interaction chromatography 55–59 can also be useful in the study of conformational changes in proteins. 60–67 The past 40 years have provided an increase in the sophistication of the tech-nologies available to measure conformational change in proteins; there has not been an increase in the parameters measured. Kauzmann 68 proposed a classification sys-tem for the levels of conformation similar to the general classification of primary, secondary, tertiary, and quaternary structure, which separated conformation issues into shape properties and short-range properties. Shape properties (long-range) were parameters dependent on the overall shape (globular, rod, etc.), which might be rela-tively insensitive to changes in the immediate vicinity of amino acids and peptide bonds. Short-range properties include parameters defined by the immediate envi-ronment around individual amino acid residues. Granted that this is an imperfect separation, it does prove useful.
eBook - PDFQuantum Chemistry
Molecules for Innovations
- Tomofumi Tada(Author)
- 2012(Publication Date)
- IntechOpen(Publisher)
A. (1996). Systematic search in Conformational Analysis. Theochem-Journal of Molecular Structure , 370 (2-3), 157-171. Po Box 211, 1000 Ae Amsterdam, Netherlands: Elsevier Science Bv. Biarnés, X., Bongarzone, S., Vargiu, A. V., Carloni, P., & Ruggerone, P. (2011). Molecular motions in drug design: the coming age of the metadynamics method. Journal of computer-aided molecular design , 25 (5), 395-402. doi:10.1007/s10822-011-9415-3 Brodmeier, T., & Pretsch, E. (1994). Application of genetic algorithms in molecular modeling. Journal of Computational Chemistry , 15 (6), 588-595. doi:10.1002/jcc.540150604 Bruni, A. T., Leite, V. B. P., & Ferreira, M. M. C. (2002). Conformational Analysis: A new approach by means of chemometrics. Journal Of Computational Chemistry , 23 (2), 222-236. Commerce Place, 350 Main St, Malden 02148, MA USA: Wiley-Blackwell. doi:10.1002/jcc.10004 Bruni, A. T., & Ferreira, M. M. C. (2008). Theoretical study of omeprazole behavior: Racemization barrier and decomposition reaction. International Journal of Quantum Chemistry , 108 (6), 1097-1106. doi:10.1002/qua.21597 Bruni, A. T., & Ferreira, M. M. C. (2002). Omeprazole and analogue compounds: a QSAR study of activity againstHelicobacter pylori using theoretical descriptors. Journal of Chemometrics , 16 (8-10), 510-520. doi:10.1002/cem.737 Brush, S. G. (1999). Dynamics of Theory Change in Chemistry : Part 1 . The Benzene Problem 1865 – 1945. Science , 30 (1), 21-79. Quantum Chemistry – Molecules for Innovations 128 Cintas, P. (2007). Tracing the origins and evolution of chirality and handedness in chemical language. Angewandte Chemie (International ed. in English) , 46 (22), 4016-24. doi:10.1002/anie.200603714 Das, G., Gentile, F., Coluccio, M. L., Perri, a M., Nicastri, a, Mecarini, F., Cojoc, G., et al. (2011). Principal component analysis based methodology to distinguish protein SERS spectra. Journal of Molecular Structure , 993 (1-3), 500-505.
eBook - ePubPeptides
Synthesis, Structures, and Applications
- Bernd Gutte(Author)
- 1995(Publication Date)
- Academic Press(Publisher)
Thus, any force field developed for the description of peptide systems is only an approximation of real intramolecular interactions. This approximation can be calibrated to reproduce vibrational spectra, relative energetics of conformational minima, and rates of conformational transitions. Despite the limitations which curtail exact quantitative applications, molecular mechanics can provide three-dimensional insight as the geometric relations between molecules are adequately represented. Electrical field potentials can be calculated and compared to give a qualitative basis for rationalizing differences in activity. Molecular modeling and its graphical representation allow the chemist to explore the three-dimensional aspects of molecular recognition and to generate hypotheses which lead to design and synthesis of new ligands. The more accurate the representation of the potential surface of the molecular system under investigation, the more likely that the modeling studies will provide qualitatively correct solutions. Once a proper set of parameters for the system under study has been selected, the force field provides the fundamental basis for simulating the system either through Newtonian mechanics or molecular dynamics, or through a stochastic generation of the relevant partition function, by Monte Carlo simulations.B. Conformational Analysis
Whereas interaction with a receptor will certainly perturb the conformational energy surface of a flexible peptide, high affinity would suggest that the peptide binds in a conformation which is not exceptionally different from one of its low-energy conformers (i.e., conformers whose energy is not dramatically higher than that of the global minimum-energy conformer). By determining the set of low-energy conformers, one attempts to generate a description of the equilibrium states of a peptide and to avoid the limitations inherent in static representations of the conformational possibilities of a peptide. Mapping the energy surface of the peptide in isolation to determine the low-energy conformers will, at the very least, provide a set of candidate conformations for consideration, or as starting points for further analyses.
eBook - PDFConformational Analysis of Polymers
Methods and Techniques for Structure-Property Relationships and Molecular Design
- Yuji Sasanuma(Author)
- 2023(Publication Date)
- Wiley(Publisher)
1 Part I Fundamentals of Polymer Physical Chemistry Conformational Analysis of Polymers: Methods and Techniques for Structure-Property Relationships and Molecular Design, First Edition. Yuji Sasanuma. © 2023 John Wiley & Sons, Inc. Published 2023 by John Wiley & Sons, Inc. 3 1 Stereochemistry of Polymers 1.1 Configuration It is well known that the direction, position, and length of a side chain, arrange- ments of the side chains, and connection ways of monomeric units significantly influence the conformational characteristics and spatial shape of the polymer. Such structural characteristics of polymers are generally termed configurations. In Oxford Advanced Learner’s Dictionary, the word “configuration” is explained as follows: an arrangement of the parts of something or a group of things; the form or shape that this arrangement produces. If the monomeric unit has a chiral center, it is assigned to either R or S enantiomer. Whether the monomeric unit is R or S will be due to the chirality of the monomer itself and the mechanism of polymerization. Besides, the chain dimension is often termed spatial config- uration, which will be determined by the conformational sequence along the polymeric chain. It should be noted that the word “configuration” has been used in different senses in polymer chemistry. Figure 1.1 represents vinyl polymers such as polypropylene (R = CH 3 ), poly(vinyl chloride) (R = Cl), and polystyrene (R = C 6 H 5 ). When the polymeric chain in the all-trans form is put on the paper so that the methine carbon is located below as in Figure 1.1, and if the side chain R appears on the front or back side of the paper, the arrangement is defined as d or l form, respectively. As illustrated on the right of Figure 1.1, if the polymeric chain of all-d configuration (above) is rotated around the central arrow by 180 ∘ , it will be the all-l structure (below). Such d and l definitions are temporary, thus designated as Flory’s pseudoasymmetry [140].
- Timir Tripathi, Vikash Kumar Dubey, Timir Tripathi, Vikash Kumar Dubey(Authors)
- 2022(Publication Date)
- Academic Press(Publisher)
Chapter 12: Experimental techniques to study protein dynamics and conformations
Akshita Gupta; Anamika Singh; Nabeel Ahmad; Tej P. Singh; Sujata Sharma; Pradeep Sharma Department of Biophysics, All India Institute of Medical Sciences, New Delhi, IndiaAbstract
Proteins are flexible biomolecules and can adopt a wide range of structural conformations such that they can have their whole conformational ensemble. Understanding of protein function is not complete without proper knowledge of protein dynamics. The nature of these structural transitions, their probabilities, and the time span for each conformation is decided by the relative free energy landscape. Protein dynamics and conformational transitions have become a research hotspot for many human diseases. Many biological phenomena like the interaction between proteins, protein, and DNA, and protein and ligand, require detailed information on protein dynamics and conformations. Various biophysical techniques such as nuclear magnetic resonance, cryo-EM, small-angle X-ray scattering, mass spectrometry, atomic force microscopy and single-molecule fluorescence resonance energy transfer, etc., are used to study the pH, temperature, or ligand-induced conformational modulations. Some of these have emerged and advanced as major tools to study molecular interactions; however, certain limitations still exist in detailing the atomic level information. In this chapter, experimental methods to study protein conformational dynamics along with specific case studies are described. These techniques offer an overall view of what happens to the structure of a protein when it performs its biological function.Keywords
Proteins; Dynamics; Conformational transitions; Nuclear magnetic resonance; Cryo-EM; Small-angle X-ray scattering; Mass spectrometry; Atomic force microscopy; Single-molecule fluorescence resonance energy transfer1: Introduction
Proteins are the primary molecular machines of biological systems. They are widely studied in terms of both structure and function. Proteins fold into specific three-dimensional (3D) structures, which are determined by their amino acid sequences.1 Protein conformation is usually defined as the spatial arrangement of its constituent atoms, which determine the overall shape of the macromolecule. However, proteins are not rigid molecules; they change their conformations rapidly in a solution linked to their biological functions. Some of the most striking examples of protein dynamics and conformational changes include protein folding and unfolding, catalysis, mediation of cell motility, transport through membranes, cell replication, transcription and translation, and assembly and disassembly of protein complexes in general.2
eBook - PDFConformational Analysis
Scope and present limitations
- G Chiurdoglu(Author)
- 2012(Publication Date)
- Academic Press(Publisher)
(2) Semi-empirical quantum mechanical treatments at various levels of sophistication—extended Hückel theory (EHT) (7); semi-empirical SCF methods (Pariser-Parr-Pople (PPP) (8, 9) ; complete neglect of differential overlap (CNDO) (10) ; modified intermediate neglect of differential overlap (MINDO) (10b); electrostatic models (11). (3) Strictly ab initio SCF-LCAO-MO calculations, introducing no empirical parameters, within the Hartree-Fock (HF) one-electron scheme, or including electron correlation (use of geminals; multiconfiguration technique) (2, 3). Methods of type 1 lead to conformational information on the geometry, relative energies, etc., of various complex molecular conformations, and are practically very useful in many complicated cases, although they may be considered as quite artificial. However, the question here is getting quantita-tive information with a certain degree of confidence and not physical accuracy of the model. * We use here conformation in a very general sense for designating the various spatial arrangements of the atoms forming a molecular system, which preserve the atomic con-nections in the molecular network. Conformational Analysis is then the study of these conformations and of their interconversion paths. AB INITIO Conformational Analysis 131 Methods of type 3 are to be used when the physical origin of potential barriers, relative stabilities, etc., as well as the quantitative aspect are to be studied in terms of fundamental physical processes. Then, the physical sound-ness of the model is the problem. Finally, methods of type 2 are somewhere between these two extremes, resembling type 1 in using empirical parameters and leading to relatively quick information (although often equivocal or erroneous (12, 13)), and resembling type 3 in being based on quantum mechanics and leading to deeper physical insight (13).
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