PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Models, Molecular”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 181 records · Page 10Linked to original sources
PubMed1989

Conformational analysis and molecular modelling of the branching point of amylopectin.

The conformational properties of 6(2) alpha-D-glucosylmaltotriose have been studied using energy calculations that include van der Waals interactions, hydrogen bond stabilization, exo-anometric effect and torsional potential contributions. The calculations focused mainly on the conformational properties displayed at the alpha(1----6) linkage within the tetrasaccharide for which the conformational space is reported. The tetrasaccharide molecule was then considered as a model compound of the branching point in amylopectin. From molecular modelling, some basic structural features associated with branching were clearly established. It was found that, among the low energy arrangements, the side chain would fold back onto the main backbone, thereby producing dense three-dimensional structures in which a 'parallel' arrangement is achieved. The branching between two strands of the double helix, as found in the crystalline moiety of A and B starches, was further investigated. It was found that one particular set of conformations about the glycosidic linkages in the two different strands, could result in an arrangement such that strands could be connected through an alpha(1----6) glycosidic linkage, with a minimum of distortion. The three-dimensional features derived from the molecular modelling agree with the physical properties and mode of biogenesis within the starch granule; they are in accord with a 'cluster' type of structure.

Amylopectin↗
PubMed2000

Recent advances in structure, binding sites with ligands and pharmacological function of beta-adrenoceptors obtained by molecular biology and molecular modeling.

The structure, binding sites interacting with ligands and the physiological functions of G-protein coupled beta-adrenoceptors (beta-ARs) are being elucidated by molecular biology and molecular modeling studies. The definition given amino acid sequences of beta-ARs in molecular biology and the analysis of three-dimensional and functional binding sites interacting with ligands by molecular modeling may be important for identifying other functional beta-ARs in various tissues and discovering new drugs. Thus, this review focuses on the interaction sites for receptor-ligand and roles of functional beta-ARs as studied by molecular biology and molecular modeling.

Adrenergic beta-Agonists↗
PubMed1997

Molecular modeling study of adsorption of poly-L-lysine onto silica glass.

A research program was initiated with both experimental and computational chemistry based molecular modeling components to investigate specific amino acid-surface interactions. The experimental portion of this study, with details reported elsewhere, investigated the adsorption of selected molecular weights of poly(L-lysine) onto silica glass microspheres with the adsorption enthalpy per adsorbed mer determined to be -0.23 +/- 0.13 kcal/mol (mean +/- 95% confidence interval). Molecular modeling of this system was then conducted using two approaches: an AM1 semiempirical molecular orbital method to predict L-lysine/glass interaction energy and an MM2 molecular mechanics method to investigate the structural configuration for poly(L-lysine). The modeling predicted a minimum energy configuration of a rotational backbone structure for poly(L-lysine) with approximately one full rotation occurring about every 8 mers, and that the amine side chains of the L-lysine will hydrogen bond with the silica surface with an average adsorption energy of approximately -0.34 kcal/mol/mer. The molecular modeling results are in good agreement with the experimentally measured value and provide insights into possible molecular-level behavior which would be very difficult to determine by experimental analyses alone. This work demonstrates the use of molecular modeling in conjunction with experimental studies to investigate complex molecular interactions.

Adsorption↗
PubMedDate not supplied

Structure of human calcitonin gene-related peptide (hCGRP) and of its antagonist hCGRP 8-37 as determined by NMR and molecular modeling.

The solution structures of human calcitonin gene-related peptide (hCGRP, 37 residues) and of its antagonistic fragment hCGRP 8-37 have been determined by two-dimensional 1H nuclear magnetic resonance (NMR) spectroscopy and molecular modeling. Analysis of the double quantum filtered correlation spectroscopy, total correlation spectroscopy and nuclear Overhauser enhancement spectroscopy spectra led to a complete assignment and to the identification of more than 350 intra- and interresidue connectivities for each peptide. Molecular models were calculated by molecular dynamics and energy minimization using distance constraints. The structure of hCGRP is characterized by a rigid N-terminal disulfide-bonded loop followed by helix segments (Val8-Leu16), a gamma-turn (Ser19-Gly21) and several local hydrogen-bonded patterns. The structure of hCGRP 8-37 is less defined than the structure of hCGRP and no helix structure is present. Molecular models of both peptides are consistent with the NH temperature coefficients and secondary chemical shifts of the alpha-protons. Hydrogen bonding with the disulfide-bonded ring appears to be critical for helix formation, both structural elements being essential for agonistic activity.

Amino Acid Sequence↗
PubMed1995

Hydration of alpha-maltose and amylose: molecular modelling and thermodynamics study.

Hydration of alpha-maltose and amylose were investigated using molecular modelling and thermodynamics methods. The structure and energy of hydration of three low-energy conformers of alpha-maltose were determined by the MM3 molecular mechanics method. The hydration structure was found to be sensitive to the conformation of alpha-maltose and hydration numbers 10 or 11 were estimated for the different conformers. Differential scanning calorimetry and thermogravimetric analysis were used to determine the number of water molecules specifically bonded (non-freezing water) to amylose and different samples of alpha-maltose. Due to high crystallinity of alpha-maltose samples, the observed non-freezing water content was lower than predicted by molecular modelling. In contrast, the experimental number of non-freezing molecules of water per D-glucopyranose residue for amorphous amylose (nh = 3.8) is in good accordance with the value of 3.8 extracted from our calculations.

Adsorption↗
PubMedDate not supplied

Molecular modeling of hapten structure and relevance to broad specificity immunoassay of sulfonamide antibiotics.

Molecular modeling of hapten structure was used to predict and influence, through appropriate synthetic work, the outcome of an immunization program. Examination of the structures of sulfonamide antibiotics led to the development of a hypothesis and the consequent synthesis of a sulfacetamide-protein immunogen aimed at the generation of broad specificity anti-sulfonamide antibodies. The antisera generated, alongside anti-sulfachlorpyradizine antisera generated at the same time, were characterized for cross-reactions against a range of sulfonamide drugs, and were found to exhibit good but not the desired broad specificity. Discussion is presented as to the reasons for the failure of the hypothesis. Further hypotheses are developed and speculation is made as to the future of molecular modeling in immunochemical research.

Animals↗
PubMed1997

Use of T cell receptor/HLA-DRB1*04 molecular modeling to predict site-specific interactions for the DR shared epitope associated with rheumatoid arthritis.

OBJECTIVE: To use molecular modeling tools to analyze the potential structural basis for the genetic association of rheumatoid arthritis (RA) with the major histocompatibility complex (MHC) "shared epitope," a set of conserved amino acid residues in the third hypervariable region of the DRbeta chain. METHODS: Homology model building techniques were used to construct molecular models of the arthritis-associated DRB1*0404 molecule and a T cell receptor (TCR) from T cell clone EM025, which is specific for DR4 molecules containing the shared epitope sequence. Interactive graphics techniques were used to orient the TCR on the DR molecule, guided by surface complementarity analysis. RESULTS: The predicted TCR-MHC-peptide complex involved multiple interactions and specificity for the shared epitope. TCR residues CDR1beta D30, CDR2beta N51, and CDR3beta Q97 were positioned to potentially participate in hydrogen bond interactions with the shared epitope DRbeta residues Q70 and R71. CONCLUSION: These results suggest a structural mechanism in which specific TCR recognition and possibly Vbeta selection are directly influenced by the disease-associated MHC polymorphisms.

Amino Acid Sequence↗
PubMed2002

Identification of binding sites of prazosin, tamsulosin and KMD-3213 with alpha(1)-adrenergic receptor subtypes by molecular modeling.

This investigation was performed to assess the importance of interaction in the bindings of selective and nonselective alpha(1)-antagonists to alpha(1)-adrenergic receptor (alpha(1)-AR) subtypes using molecular modeling. The alpha(1)-antagonists used in this study were prazosin, tamsulosin and KMD-3213. Molecular modeling was performed on Octane 2 workstation (Silicon Graphics) using Discover/Insight II software (Molecular Simulations Inc.). Through molecular modeling, possible binding sites for these drugs were suggested to lie between transmembrane domains (TM) 3, 4, 5 and 6 of the alpha(1)-AR subtypes. In prazosin, the 4-amino group, 1-nitrogen atom and two methoxy groups of quinazoline ring possibly interact with the amino acids in TM3, TM5 and TM6 of alpha(1)-ARs. In tamsulosin, amine group of ethanyl amine chain, methoxy group of benzene ring and sulfonamide nitrogen of benzene ring interacts in TM3, TM4 and TM5 of alpha(1)-ARs. In KMD-3213, amine of ethyl amine chain and indoline nitrogen of this compound possibly interact within TM3 and TM5 of alpha(1)-ARs. Amide nitrogen of KMD-3213 also interacts within TM4 of alpha(1A)-AR. The results of the present study suggested that prazosin has similar binding sites in all the alpha(1)-AR subtypes while tamsulosin interacts at higher number of sites with alpha(1D)-subtype than other alpha(1)-AR subtypes. KMD-3213 being an alpha(1A)-AR selective ligand, binds to higher number of sites of alpha(1A) subtype than to other subtypes. All these amino acids are located near the extracellular loop. These findings are consistent with the previous studies that antagonists bind higher in the pocket closer to the extracellular surface unlike agonist binding.

Adrenergic alpha-Antagonists↗
PubMedDate not supplied

Molecular modelling of MHC class I carbohydrates.

In this article we present the results of molecular modelling of four complex carbohydrates which have been found in the MHC class I proteins. Though these proteins show diversity in their sequences, the glycosylation sites are highly conserved indicating a possible structural/functional role of the glycan chain. Similar glycan chains have been found linked with other proteins of completely different function, such as IgG, and erythropoeitin. Thus, the molecular modelling of these carbohydrates will not only provide structural/dynamic information of these complex molecules but will also provide conformational information which can be utilised to build the glycoprotein models. The results presented here indicate that although several linkages show less conformational flexibility, terminal linkages can be quite flexible.

Carbohydrate Conformation↗
PubMed2003

Molecular modelling of human CYP1B1 substrate interactions and investigation of allelic variant effects on metabolism.

Molecular modelling of human CYP1B1 based on homology with the mammalian P450, CYP2C5, of known three-dimensional structure is reported. The enzyme model has been used to investigate the likely mode of binding for selected CYP1B1 substrates, particularly with regard to the possible effects of allelic variants of CYP1B1 on metabolism. In general, it appears that the CYP1B1 model is consistent with known substrate selectivity for the enzyme, and the sites of metabolism can be rationalized in terms of specific contacts with key amino acid residues within the CYP1B1 heme locus. Furthermore, a mode of binding interaction for the inhibitor, alpha-naphthoflavone, is presented which accords with currently available information. The current paper shows that a combination of molecular modelling and experimental determinations on the substrate metabolism for CYP1B1 allelic variants can aid in the understanding of structure-function relationships within P450 enzymes.

Alleles↗
PubMed1990

Experiments with a universe for molecular modelling of biological processes.

A computer simulation program and results of preliminary simulations of an abstract two-dimensional universe are presented, in which biological and physical processes can be modelled at the molecular level. Two types of permanent elements (atoms) occupy squares of the universe: called 0 and 1. Atoms sharing a common square form a particle, with properties determined by its component atoms. Atoms, particles, and complexes of particles move and collide according to rules like those of classical mechanics. At a higher level of organization, the string of atoms in a particle is viewed as a program, whose execution can affect the space around the particle. The computer program (written in Turbo-Pascal language) can simulate the evolution of the universe starting from any given initial configuration of the particles. Three examples of simulations, showing the development of ordered spatial structures from initial sets of randomly distributed particles, illustrate the universe's potential in modelling various molecular processes.

Cell Wall↗
PubMed1994

Molecular modeling of steroidal estrogens: novel conformations and their role in biological activity.

Since the structure and conformation of many estrogenic ligands cannot be described with X-ray crystallographic studies, molecular modeling techniques must be used to generate their 3-dimensional structures. The potential of three molecular modeling methods to simulate the X-ray crystallographic geometry of estradiol-17 beta and various analogs (estratrien-1,17 beta-diol, estratrien-2,17 beta-diol, estratrien-3,11 alpha,17 beta-triol, estratrien-3,11 beta,17 beta-triol, 9 beta-estratrien-3,17 beta-diol-11-one) have been compared. MMP2 molecular mechanics as well as the MOPAC semi-empirical molecular orbital methods, AM1 and PM3, were examined in these studies of estrogens with unique ring distortions. Whereas all three methods were able to simulate reasonable estrogen structures, the MMP2 method was found to reproduce the X-ray geometry of estrogens better than the MOPAC methods. The contribution of crystal packing distortions on the X-ray structures in these comparisons is discussed. Additionally, a molecular modeling dynamics method for the systematic conformational searching of steroidal estrogens is presented. For each estrogen examined, conformational searching produced at least one unique steroid conformation in addition to the X-ray crystallographic geometry. The MMP2 potential energy of predicted conformations and transition barriers of these estrogens has been shown to be less than the free energy of receptor binding. Thus, it is conceivable that estrogen ligands which can exist in a number of conformations may be converted to a preferred geometry by binding within the specific site of receptor. Furthermore, it is suggested that conformational flexibility of estrogens may be an important property of specific ligands for the estrogen receptor.

Crystallography, X-Ray↗
PubMed2004

Molecular modeling and small angle X-ray scattering studies of Hoplosternum littorale cathodic haemoglobin.

Considerable interest is currently focused on fish haemoglobins in order to identify the structural basis for their diversity of functional behavior. Hoplosternum littorale is a catfish that presents bimodal gill (water)/gut (air)-breathing, which allows this species to survive in waters with low oxygen content. The hemolysate of this fish showed the presence of two main haemoglobins, cathodic and anodic. This work describes structural features analyzed here by integration of molecular modeling with small angle X-ray scattering. Here is described a molecular model for the cathodic haemoglobin in the unliganded and liganded states. The models were determined by molecular modeling based on the high-resolution crystal structure of fish haemoglobins. The structural models for both forms of H. littorale haemoglobin were compared to human haemoglobin.

Amino Acid Sequence↗
PubMed2002

A review of molecular modeling approaches to pharmacophore models and structure-activity relationships of ion channel modulators in CNS.

Through pharmacophore models and providing quantitative analysis of structure-activity relationships (QSAR), molecular modeling techniques can be useful tools to study the interactions of ion channels and their modulators. The present review focuses on molecular modeling approaches that defined pharmacophore models of ion channel modulators in the CNS. The commonality and subtlety of the pharmacophore models of various ion channel modulators are discussed which can be used as a framework for the design of ion channel modulators.

Central Nervous System↗
PubMed1989

[Molecular modeling of anti-arrhythmia agents in class Ia and Ib--model conceptions of different binding receptors].

The molecular properties of quinidine, EO 122, and lidocaine were investigated using theoretical methods (Molecular Modeling). The binding pattern of the molecules were investigated by calculating interaction energies with a negative charged fragment (receptor model). Based on these calculations a model for the differentiation of class Ia and class Ib antiarrhythmic drugs could be deduced. The results explain data which were formulated in the modulated receptor hypothesis. In this way the molecular basis for the preferred affinity of quinidine to the open state of the sodium channel as well as the equal affinity of lidocaine to the open and inactivated state of the channel were defined.

Anti-Arrhythmia Agents↗
PubMed2005

Iron affects the structure of cell membrane molecular models.

The effects of Fe(3+) and Fe(2+) on molecular models of biomembranes were investigated. These consisted of bilayers of dimyristoylphosphatidylcholine (DMPC) and of dimyristoylphosphatidylethanolamine (DMPE), classes of phospholipids located in the outer and inner moieties of cell membranes, respectively. X-ray studies showed that very low concentrations of Fe(3+) affected DMPC organization and 10(-3)M induced a total loss of its multilamellar periodic stacking. Experiments carried out with Fe(2+) on DMPC showed weaker effects than those induced by Fe(3+) ions. Similar experiments were performed on DMPE bilayers. Fe(3+) from 10(-7)M up to 10(-4)M had practically no effect on DMPE structure. However, 10(-3)M Fe(3+) induced a deep perturbation of the multilamellar structure of DMPE. However, 10(-3)M Fe(2+) had no effect on DMPE organization practically. Differential scanning calorimetry measurements also revealed different effects of Fe(3+) and Fe(2+) on the phase transition and other thermal properties of the examined lipids. In conclusion, the results obtained indicate that iron ions interact with phospholipid bilayers perturbing their structures. These findings are consistent with the observation that iron ions change cell membrane fluidity and, therefore, affect its functions.

Calorimetry, Differential Scanning↗
PubMed2004

Molecular modeling of sigma 1 receptor ligands: a model of binding conformational and electrostatic considerations.

We have performed molecular modeling studies on several sigma 1 specific ligands, including PD144418, spipethiane, haloperidol, pentazocine, and others to develop a pharmacophore for sigma 1 receptor-ligand binding, under the assumption that all the compounds interact at the same receptor binding site. The modeling studies have investigated the conformational and electrostatic properties of the ligands. Superposition of active molecules gave the coordinates of the hypothetical 5-point sigma 1 pharmacophore, as follows: R1 (0.85, 7.26, 0.30); R2 (5.47, 2.40, -1.51); R3 (-2.57, 4.82, -7.10); N (-0.71, 3.29, -6.40); carbon centroid (3.16, 4.83, -0.60), where R1, R2 were constructed onto the aromatic ring of each compound to represent hydrophobic interactions with the receptor; and R3 represents a hydrogen bond between the nitrogen atom and the receptor. Additional analyses were used to describe secondary binding sites to electronegative groups such as oxygen or sulfur atom. Those coordinates are (2.34, 5.08, -4.18). The model was verified by fitting other sigma 1 receptor ligands. This model may be used to search conformational databases for other possibly active ligands. In conjunction with rational drug design techniques the model may be useful in design and synthesis of novel sigma 1 ligands of high selectivity and potency. Calculations were performed using Sybyl 6.5.

Binding Sites↗