[Show abstract][Hide abstract] ABSTRACT: We present a molecular dynamics (MD) study on a series of helical arylamide oligomers with systematically varying building blocks and linkage types. This study showcases a computational approach for the prediction of secondary structure properties of arylamide foldamers and their solution dynamics. We demonstrate that conformational characteristics of foldamers, such as number of units per turn, helical pitch, and pore diameter, can be predicted by MD simulations of small oligomers significantly shorter than the foldamers in question. Importantly, the curvature angle, the key geometrical parameter in helical arylamide structures, can be accurately determined by MD simulation of tetramers, entities with often less than one helical turn. The curvature angle is found to be a local property associated with one single residue/unit, which enables highly accurate predictive power for designing oligomers with various scaffolds and sizes. In addition, MD simulations with the improved force field parameters capture solvent effects in terms of both protic solvent competition with intramolecular H-bonds and solvophobic effects. The computational approach can provide useful insight into dynamical, mechanistic and functional properties of the arylamide oligomer class, which will facilitate rational design of foldamers.
New Journal of Chemistry 03/2015; 39(5). DOI:10.1039/C4NJ01925C · 3.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Molecular capsules have been extensively used in catalysis, drug delivery, molecular recognition and protection of ligands from degradation. Novel "apple peel" shaped helical arylamide capsules have been experimentally pursued due to their flexible nature and designability. They were found to encapsulate a variety of small molecules. The apple peel shape of the capsules led to a hypothesis that binding and release of ligands involve partial unfolding. However, the exact mechanism is unknown. Using molecular dynamics simulations with our new aryl-amide force field parameters, we identify two low energy barrier binding/release mechanisms, in which the capsule's helical structure is either minimally disturbed or restored quickly (within 100 ps). Furthermore, we determine the effects of ligand sizes, their chemical nature (hydrogen bonding capabilities), and solvents on binding modes and stabilities. Our findings not only support experimental observations but also provide underlying principles that allow for rational design of foldamer capsules.
[Show abstract][Hide abstract] ABSTRACT: We examine the conformational preferences of the furan- and thiophene-based arylamides, N-methylfuran-2-carboxamide () and N-methylthiophene-2-carboxamide (), using a combination of computational methods and NMR experiments. The compound choice stems from their use as foldamer building blocks. We quantify the differences in the conformational rigidity of the two compounds, which governs corresponding foldamer conformations. Specifically, we demonstrate the effects of intramolecular hydrogen bonding (H-bonding), geometrical patterns and solvent polarity on arylamide conformations by comparing , and previously studied ortho-methoxy N-methylbenzamide () and ortho-methylthio N-methylbenzamide (). The study reveals that compound , despite its non-optimal S(5)-type H-bond geometry, retains a large portion of the H-bonded (eclipsed) conformation even in polar protic solvents. This behaviour is consistent with the quantum mechanical (QM) torsional energy profile. The percentages of H-bonded conformers that retains are just slightly smaller than those of , which has a stronger S(6)-type H-bond. As for and , the replacement of the O atom in by an S atom in results in a 70-90% loss of the H-bonded conformer in solution. However, the equivalent O to S replacement in (leading to ) causes only 15-30% loss of the eclipsed conformers in . Therefore, conformational preferences of are very different from , in contrast to the similarity between and . This study shows how the interplay of several forces modulates the conformational flexibility of arylamides. It also attests the strategy we are developing, which leads to accurate prediction of foldamer structure. The vital component of this strategy is the re-parameterization of critical force field parameters based on QM potential energy profiles, as well as validation of these parameters using experimental data in solution.
[Show abstract][Hide abstract] ABSTRACT: The aromatic oligoamide (arylamide) foldamer class, characterized by the repetitive aromatic-amide pattern, is one of the most intensively studied foldamer families. In this article, the potential energy profiles with regard to torsional motions around the two types of aromatic-amide bonds (C(a)-C(p) and C(a)-N) are obtained at the B3LYP/6-311G(d,p) level of theory. The effect of ortho substituents with different hydrogen bonding abilities (OCH(3) vs. SCH(3) ) on the torsional potential profiles is analyzed in detail. There are several findings that have implications in foldamer design. The ortho-SCH(3) substituent on the benzene ring produces a much more flexible arylamide backbone with respect to the OCH(3) substituent, as it restricts the C(a)-C(p) torsion to a lesser extent. Interestingly, the rigidifying effect of the ortho-SCH(3) substituent on the C(a)-N torsion is very similar to that of the OCH(3) substituent on the same linkage type. In addition, the SCH(3) substituent prefers a perpendicular orientation with respect to the benzene ring to the in-plane one. It is also found that reparameterization of the corresponding torsional parameters, sometimes specific to the ortho substituent type, in the general amber force field is necessary for an accurate description of the backbone torsions in arylamides. Six sets of partial charge/torsional parameters for each linkage (C(a)-C(p) or C(a)-N)/substituent (OCH(3) or SCH(3) ) combination are obtained based on the ab initio torsional profiles. Initial assessments of these parameters show good agreement with the ab initio results.
[Show abstract][Hide abstract] ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
[Show abstract][Hide abstract] ABSTRACT: As a part of our systematic study of foldamer structural elements, we analyze and quantify the conformational behavior of two model compounds based on a frequently used class of aromatic oligoamide building blocks. Combining computational and NMR approaches, we investigate ortho-fluoro- and ortho-chloro-N-methylbenzamide. Our results indicate that the -F substituent in an ortho position can be used to fine-tune the rigidity of the oligomer backbone. It provides a measurably attenuated but still considerably strong hydrogen bond (H-bond) to the peptide group proton when compared to the -OCH3 substituent in the same position. On the other hand, the ortho-Cl substituent does not impose significant restrictions on the flexibility of the backbone. Its effect on the final shape of an oligomer is likely governed by its size rather than by noncovalent intramolecular interactions. Furthermore, the effect of solvent on the conformational preferences of these building blocks has been quantified. The number of intramolecularly H-bonded conformations decreases significantly when going from nonprotic to protic environments. This study will facilitate rational design of novel arylamide foldamers.
The Journal of Physical Chemistry B 10/2009; 113(38):12809-15. DOI:10.1021/jp905261p · 3.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We combine molecular modeling and NMR methods to better understand intramolecular hydrogen bonding (H-bonding) in a frequently used arylamide foldamer building block, ortho-methoxy-N-methylbenzamide. Our results show that solvents have a profound influence on the cumulative number and stabilizing effects of intramolecular H-bonds, and thus conformational preferences, of foldamers based on this compound. While intramolecular H-bonds are conserved in aprotic environments, they are significantly disrupted in protic solvents. Furthermore, these solvent effects can be accurately quantified using the computational approach presented here. The results could have significant implications in foldamer design, particularly for applications in aqueous environments.
The Journal of Physical Chemistry B 05/2009; 113(20):7041-4. DOI:10.1021/jp902155j · 3.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite widespread zirconium use ranging from nuclear technology to antiperspirants, important aspects of its solvation chemistry, such as the nature of small zirconium(IV) hydroxy cluster ions in aqueous solution, are not known due to the complexity of the zirconium aqueous chemistry. Using a combination of Car−Parrinello molecular dynamics simulations and conventional quantum mechanical calculations, we have determined the structural characteristics and analyzed the aqueous solution dynamics of the two smallest zirconium(IV) cluster species possible, i.e., the dimer and trimer. Our study points to and provides detailed geometrical information for a stable structural motif for building zirconium polymers, the Zr(OH)2Zr bridging unit with 7−8 coordinated Zr ions, which, however, cannot be used to construct a stable structure for the trimer. We find that a stacked trimer, not featuring this motif, is a possible structure, though not a very stable one, shedding new light on this species, and its possible importance in the aqueous chemistry of Zr4+ ion.
Journal of Chemical Theory and Computation 12/2007; 4(1). DOI:10.1021/ct7001094 · 5.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Zr(4+) tetramer, [Zr(4)(OH)(8)(H(2)O)(16)](8+), is thought to be the major component of the Zr(4+) polymer system in aqueous solution, present as a dominant ionic cluster species compared to other Zr(4+) clusters under various experimental conditions. Despite widespread applications of zirconium, the structure and dynamics of the tetramer in aqueous solution are not well understood. We conducted a combination of ab initio molecular dynamics and quantum mechanical studies in the gas phase and aqueous solution and related our results to the available experimental data to provide atom-level information on the behavior of this species in aqueous solution. Our simulations indicate that the tetramer structure is stable on the picosecond time scale in an aqueous environment and that it is of a planar form, comprising eight-coordinated Zr(4+) ions with an antiprism/irregular dodecahedron ligand arrangement. In combination with our studies of Zr(4+) dimer and trimer clusters, our results provide detailed geometrical information on structural motifs for building zirconium polymers and suggest a possible polymerization path.
The Journal of Physical Chemistry A 12/2007; 111(45):11395-9. DOI:10.1021/jp0734880 · 2.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Using DFT methods, we have determined intramolecular parameters for an important class of arylamide polymers displaying antimicrobial and anticoagulant inhibitory properties. A strong link has been established between these functions and the conformation that the polymers adopt in solution and at lipid bilayer interfaces. Thus, it is imperative for molecular dynamics simulations designed to probe the conformational behavior of these systems to accurately describe the torsional degrees of freedom. Standard force fields were shown to be deficient in this respect. Therefore, we have computed the relevant torsional energy profiles using a series of constrained geometry optimizations. We have also determined electrostatic parameters using our results in combination with standard RESP charge optimization. Force constants for bond and angle potentials were calculated by iteratively matching quantum and classical normal modes via a Monte Carlo scheme. The resulting new set of parameters accurately described the conformation and dynamical behavior of the arylamide polymers.
[Show abstract][Hide abstract] ABSTRACT: Using quantum chemistry plus ab initio molecular dynamics and classical molecular dynamics methods, we address the relationship between molecular conformation and the biomedical function of arylamide polymers. Specifically, we have developed new torsional parameters for a class of these polymers and applied them in a study of the interaction between a representative arylamide and one of its biomedical targets, the anticoagulant drug heparin. Our main finding is that the torsional barrier of a C(aromatic)-C(carbonyl) bond increases significantly upon addition of an o-OCH2CH2NH3+ substituent on the benzene ring. Our molecular dynamics studies that are based on the original general AMBER force field (GAFF) and GAFF modified to include our newly developed torsional parameters show that the binding mechanism between the arylamide and heparin is very sensitive to the choice of torsional potentials. Ab initio molecular dynamics simulation of the arylamide independently confirms the degree of flexibility we obtain by classical molecular dynamics when newly developed torsional potentials are used.
The Journal of Physical Chemistry B 04/2006; 110(8):3517-26. DOI:10.1021/jp054306+ · 3.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have applied molecular dynamics to investigate the structural properties and activity of recently synthesized amphiphilic polymethacrylate derivatives, designed to mimic the antimicrobial activity of natural peptides. The composition, molecular weight, and hydrophobicity (ratio of hydrophobic and cationic units) of these short copolymers can be modulated to achieve structural diversity, which is crucial in controlling the antimicrobial activity. We have carried out all-atom molecular dynamics to systematically investigate the conformations adopted by these copolymers in water and at the water-lipid interface as a function of sequence and the chemical nature of the monomers. For two sequences, we observe partial insertion into the bilayer. Formation of strong interactions between the lipid headgroups and the amine groups of the polymers assists in the initial association with the lipids. However, the primary driving force for the observed partial insertion appears to be the hydrophobic effect. Our results indicate sensitive dependence of the overall shape on the sequence, suggesting that experimentally observed changes in activity can be correlated with particular sequences, providing an avenue for rational design.
Journal of the American Chemical Society 03/2006; 128(6):1778-9. DOI:10.1021/ja0564665 · 12.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Kontrolle über den Blutverlust: Die Wechselwirkung der Arylamidoligomere 1, deren Synthese hier vorgestellt wird, mit Heparin inhibiert die Fähigkeit von Heparin, Antithrombin zu aktivieren. Diese Arylamidoligomere sind die ersten Beispiele für niedermolekulare Antagonisten, die die antikoagulierende Wirkung von Heparin inhibieren.