Michaela Knapp-Mohammady

Energetics and structure of glycine and alanine based model peptides: Approximate SCC-DFTB, AM1 and PM3 methods in comparison with DFT, HF and MP2 calculations

We calculate relative energies and geometries of important secondary structural elements for small glycine and alanine based polypeptides containing up to eight residues. We compare the performance of the approximate methods AM1, PM3 and self-consistent charge, density-functional tight-binding (SCC-DFTB) to density-functional theory (DFT), Hartree‐Fock (HF) and MP2. The SCC-DFTB is able to reproduce structures and relative energies of various peptide models reliably compared to DFT results. The AM1 and PM3 methods show deficiencies in describing important secondary structure elements like extended, helical or turn structures. The discrepancies between diAerent ab initio (HF, MP2) and DFT (B3LYP) methods for medium sized basis sets (6-31G*) also show the need for higher level calculations, since systematic errors found for small molecules may add up when investigating longer polypeptides. ” 2001 Elsevier Science B.V. All rights reserved.

L-Alanyl-L-alanine in the zwitterionic state: structures determined in the presence of explicit water molecules and with continuum models using density functional theory

Abstract The structures and relative energies for L-alanyl-L-alanine (LALA) in the presence of explicit water molecules have been determined by using the density functional theory (DFT) Becke3–Lee–Yang–Parr functional and the 6-31G* basis set (B3LYP/6-31G*). In aqueous solution the dominant state of LALA is the zwitterionic form, while its neutral form is dominant in vacuo. Attempts to locate or determine a gas-phase zwitterionic species failed. That is, on the B3LYP/6-31G* potential energy surface, there is no barrier to proton transfer from the positively charged ammonium group to the negatively charged carboxylate group, or from the ammonium group to the adjacent carbonyl oxygen and from the amide nitrogen to the carboxylate group. To stabilize the zwitterion, we modelled the system by adding explicit water molecules and by placing the zwitterion within a sphere surrounded by a medium with a dielectric constant of 78.5, that is, within the Onsager continuum model, where the recommended cavity radius is obtained from a solute volume calculation. The zwitterionic species is only stable in the presence of water at the B3LYP/6-31G* level. This makes it imperative to include water molecules to model the zwitterionic species of LALA, peptides and amino acids at the B3LYP/6-31G* level. Finally, the zwitterionic structure stabilized by explicit water molecules has also been modelled within the Onsager theory. Here the Onsager model represents the effects due to the bulk water and the explicit water molecules stand for the effect due to direct H-bonding between the zwitterion and the solvent, that is, the first solvation shell. We used molecular dynamics simulations utilizing the CHARMm force field to produce structural input for the subsequent quantum-mechanical simulations. The structures determined using various methods to model the LALA zwitterionic form in aqueous solution were compared. We were able to find additional stable structures for LALA by adding water molecules and optimizing it which could not be obtained by using the Onsager theory. This shows that one must be careful when using continuum models to study peptides and proteins or other methods which do not take into account the explicit interactions between the solute and the first solvent shell.

Effect of the His residue on the cyclization of b ions.

The MSn spectra of the [M + H]+ and b5 peaks derived from the peptides HAAAAA, AHAAAA, AAHAAA, AAAHAA, and AAAAHA have been measured, as have the spectra of the b4 ions derived from the first four peptides. The MS2 spectra of the [M + H]+ ions show a substantial series of bn ions with enhanced cleavage at the amide bond C-terminal to His and substantial cleavage at the amide bond N-terminal to His (when there are at least two residues N-terminal to the His residue). There is compelling experimental and theoretical evidence for formation of nondirect sequence ions via cyclization/reopening chemistry in the CID spectra of the b tons when the His residue is near the C-terminus. The experimental evidence is less clear for ions when the His residue is near the N-terminus, although this may be due to the use of multiple alanine residues in the peptide making identifying scrambled peaks more difficult. The product ion mass spectra of the b4 and b5 ions from these isomeric peptides with cyclically permuted amino acid sequences are similar, but also show clear differences. This indicates less active cyclization/reopening followed by fragmentation of common structures for bn ions containing His than for sequences of solely aliphatic residues. Despite more energetically favorable cyclization barriers for the b5 structures, the b4 ions experimental data show more clear evidence of cyclization and sequence scrambling before fragmentation. For both b4 and b5 the energetically most favored structure is a macrocyclic isomer protonated at the His side chain.

A theoretical study of structures and electron affinities of radical anions of guanine-cytosine, adenine-thymine, and hypoxanthine-cytosine base pairs

Adiabatic electron affinities (AEA) and structural perturbations due to addition of an excess electron to each of the neutral guanine‐cytosine (G‐C), adenine‐thymine (A‐T), and hypoxanthine‐cytosine (HX‐C) base pairs were studied using the self‐consistent charge, density functional tight‐binding (SCC‐DFTB‐D) method, augmented by the empirical London dispersion energy term. Performance of the SCC‐DFTB‐D method was examined by comparing the calculated results using it with those obtained from experiment as well as ab initio and other different density functional theoretical studies. An excellent agreement between the SCC‐DFTB‐D results and those obtained by the other calculations regarding the structural modifications, hydrogen bonding, and dissociation energies of the neutral and radical anion base pairs was found. It is shown that adiabatic electron affinity can be better predicted by considering reaction enthalpies of formation of the respective neutral and anionic base pairs from their respective molecular components instead of taking the difference between their total energies. The calculated AEAs of the base pairs were compared with those obtained by the bracketing method from Schaefer and coworkers, where a satisfactory agreement was found. It shows applicability of the SCC‐DFTB‐D method to study charged DNA models at a highly economical computational cost.

Fragmentation of Doubly-Protonated Pro-His-Xaa Tripeptides: Formation of b22+ Ions

When ionized by electrospray from acidic solutions, the tripeptides Pro-His-Xaa (Xaa=Gly, Ala, Leu) form abundant doubly-protonated ions, [M+2H]2+. Collision-induced dissociation (CID) of these doubly-protonated species results, in part, in formation of b22+ ions, which fragment further by loss of CO to form a22+ ions; the latter fragment by loss of CO to form the Pro and His iminium [immonium is commonly used in peptide MS work] ions. Although larger doubly-charged b ions are known, this represents the first detailed study of b22+ ions in CID of small doubly protonated peptides. The most abundant CID products of the studied doubly-protonated peptides arise mainly in charge separation involving two primary fragmentation channels, formation of the b2/y1 pair and formation of the a1/y2 pair. Combined molecular dynamics and density functional theory calculations are used to gain insight into the structures and fragmentation pathways of doubly-protonated Pro-His-Gly including the energetics of potential protonation sites, backbone cleavages, post-cleavage charge-separation reactions and the isomeric structures of b22+ ions. Three possible structures are considered for the b22+ ions: the oxazolone, diketopiperazine, and fused ring isomers. The last is formed by cleavage of the His-Gly amide bond on a pathway that is initiated by nucleophilic attack of one of the His side-chain imidazole nitrogens. Our calculations indicate the b22+ ion population is dominated by the oxazolone and/or fused ring isomers.

Aqueous microdroplet encapsulation of normal or cancerous single cells

Microdroplet encapsulation of normal or cancerous single cells has by now been achieved experimentally. Here we focus on one important approach advocated by Chabert and Viovy [Proc. Nat. Acad. Sci. U.S.A. 105, 3191 (2008)]; see also Dupin et al. [Dupin, Halliday, and Care, Phys. Rev. Ser. E 73, 055701 (2006); Philos. Trans. R. Soc. London Ser. A 362, 1885 (2004)]. One can encapsulate a single cell in an appropriate microdroplet with volume kept to a minimal value (e.g. from two to eight times the initial volume of the cell). We refer then specifically to the sorting of the cells from blood, an example discussed in Chabert and Viovy (2008). As Chabert and Viovy emphasise and as is very important for this article, the membrane of the cell remains intact following the encapsulation procedure within a microdroplet. So it may be of interest to explore further experimental techniques which we refer to briefly, if these are feasible to study anomalous diffusion, especially in encapsulated cell membranes. Finally, it is to be hoped that the current controversy concerning the relevance of fractal geometry to understanding the range of size of organisms can be resolved. The authors of this article take the view that there are experimental foundations in biology to support the use of fractal geometry.

Exchange energy density and exchange potential via a hartree–fock plus mp2 study of the electron liquid in the ground-state conformer of glycine

Very recent criticisms of existing exchange-correlation functionals by Wanko et al. applied to systems of biological interest have led us to reopen the question of the ground-state conformer of glycine: the simplest amino acid. We immediately show that the global minimum of the Hartree–Fock (HF) ground-state leads to a planar structure of the five non-hydrogenic nuclei, in the non-ionized form NH2–CH2–COOH. This is shown to lie lower in energy than the zwitterion structure NHB3 +–CH2–COO−, as required by experiment. Refinement of the nuclear geometry using second-order Møller–Plesset perturbation theory (MP2) is also carried out, and bond lengths are found to accord satisfactorily with experimentally determined values. The ground-state electron density for the MP2 geometry is then redetermined by HF theory and equidensity contours are displayed. The HF first-order density matrix γ( r , r ′) is then used to obtain similar exchange-energy density (ε x ( r )) contours for the lowest conformer of glycine. At first sight, their shape looks almost the same as for the density ρ( r ), which seems to vindicate the LDA proportional to ρ( r )3/4. However, by way of an analytically soluble model for an atomic ion, it is shown that this has to be corrected to obtain an accurate HF exchange energy Ex as the volume integral of ε x ( r ). Finally, recognizing that for larger amino acids, the use of HF plus MP2 perturbation corrections will become prohibitive, we have used the HF information for ε x ( r ) and ρ( r ) to plot the truly non-local exchange potential proposed by Slater, from the density matrix γ( r , r ′). This latter calculation should be practicable for large amino acids, but there adopting Beckes one-parameter form of ε x ( r ) correcting LDA exchange. Some future directions are suggested.

Revised CHARMM force field parameters for iron-containing cofactors of photosystem II

Photosystem II is a complex protein–cofactor machinery that splits water molecules into molecular oxygen, protons, and electrons. All‐atom molecular dynamics simulations have the potential to contribute to our general understanding of how photosystem II works. To perform reliable all‐atom simulations, we need accurate force field parameters for the cofactor molecules. We present here CHARMM bonded and non‐bonded parameters for the iron‐containing cofactors of photosystem II that include a six‐coordinated heme moiety coordinated by two histidine groups, and a non‐heme iron complex coordinated by bicarbonate and four histidines. The force field parameters presented here give water interaction energies and geometries in good agreement with the quantum mechanical target data.

First-principles structures for the close-packed and the 7/2 motif of collagen

The recently proposed close-packed motif for collagen is investigated using first principles semi-empirical wave function theory and Kohn-Sham density functional theory. Under these refinements the close-packed motif is shown to be stable. For the case of the 7/2 motif a similar stability exists. The electronic circular dichroism of the close-packed model has a significant negative bias and a large signal. An interesting feature of the close-packed structure is the existence of a central channel. Simulations show that, if hydrogen atoms are placed in the cavity, a chain of molecular hydrogens is formed suggesting a possible biological function for molecular hydrogen.

The inhomogeneous electron liquid in some bioinorganic assemblies studied by density functional methods

The review starts with a discussion of some recent advances related to the foundations of density functional theory (DFT). Some emphasis is placed on methods which should have special relevance to bioinorganic assemblies. In particular, the inhomogeneous electron liquid in the ground state of such systems is a specific focal point. After a brief summary concerning the possible variational validity of some popular energy functionals, the future value of the important Dirac idempotent density matrix is emphasised, both from first principles and semiempirically by making use of X-ray diffraction experiments. The review concludes with two topical examples of bioinorganic assemblies. The first concerns our own work on an anticancer drug based on a Ru complex, while as a second example a recent DFT study of a molecular biosensor by K. Salazar-Salinas, L.A. Jauregui, C. Kubli-Garfias, J.M. Seminario [J. Chem. Phys. 130, 105101 (2009)] involving an Fe complex is briefly summarised.