Biomedical subjects

Anselm H C Horn

Publications and source records attributed to Anselm H C Horn.

8 recordsLinked to original sources

PubMed2006

Multipole electrostatic potential derived atomic charges in NDDO-methods with spd-basis sets.

The recently introduced multipole approach for computing the molecular electrostatic potential (MEP) within the semiempirical neglect of diatomic differential overlap (NDDO) framework [Horn AHC, Lin Jr-H., Clark T (2005) Theor Chem Acc 114:159-168] has been used to obtain atomic charges of nearly ab initio quality by scaling the semiempirical MEP. The parameterization set comprised a total of 797 compounds and included not only the newly parameterized AM1* elements Al, Si, P, S, Cl, Ti, Zr, and Mo but also the standard AM1 elements H, C, N, O and F. For comparison, the ZDO-approximated MEP was also calculated analytically in the spd-basis. For the AM1*-optimized structures, single-point calculations at the B3LYP, HF and MP2 levels with the 6-31G(d) and LanL2DZP basis sets were performed to obtain the MEP. The regression analysis of all 12 combinations of semiempirical and ab initio MEP data yielded correlation coefficients of at least 0.99 in all cases. Scaling the analytical and multipole-derived semiempirical MEP by the regression coefficients yielded mean unsigned errors below 2.6 and 1.9 kcal mol(-1), respectively. Subsequently, for 22 drug molecules from the World Drug Index, atomic charges were computed according to the RESP procedure using XX/6-31G(d) (XX=B3LYP, HF, MP2) and scaled AM1* multipole MEP; the correlation coefficients obtained are 0.83, 0.85 and 0.83, respectively.

Models, Chemical↗

PubMed2006

Insights into amprenavir resistance in E35D HIV-1 protease mutation from molecular dynamics and binding free-energy calculations.

Drug resistance is a very important factor contributing to the failure of current HIV therapies. The ability to understand the resistance mechanism of HIV-protease mutants may be useful in developing more effective and longer lasting treatment regimens. In this paper, we report the first computational study of the clinically relevant E35D mutation of HIV-1 protease in its unbound conformation and complexed with the clinical inhibitor amprenavir and a sample substrate (Thr-Ile-Met-Met-Gln-Arg). Our data, collected from 10 ns molecular-dynamics simulations, show that the E35D mutation results in an increased flexibility of the flaps, thereby affecting the conformational equilibrium between the closed and semi-open conformations of the free protease. The E35D mutation also causes a significant reduction of the calculated binding free energies both for substrate and amprenavir, thus giving a plausible explanation for its ability to increase the level of resistance. One possible explanation for the emergence of this mutation, despite its unfavorable effect on substrate affinity, might be the role of E35D as an escape mutation, which favors escape from the immune system in addition to conferring drug resistance.

Amino Acid Substitution↗

PubMed2006

Rare large scale subdomain motions in prion protein can initiate aggregation.

The prion protein is thought to induce prion diseases by changing its conformation from the cellular form, PrP(C), into the infectious Scrapie-form, PrP(Sc). Little is known about the structural and dynamical features of this conformational change. We here introduce a novel concept that involves rare large scale motions between the subdomains beta1-alpha1-beta2 and alpha2-alpha3 in the carboxy-terminal, globular part of PrP. The interface between these two subdomains carries most pathogenic mutations known to be associated with prion diseases. Based on computational simulations as well as experimental results we propose that such a large scale motion subsequently destabilizes large parts of the cellular conformer PrP(C), thus, rendering it prone to structural rearrangements, including aggregation of now partially unfolded parts of the PrP sequence. We hypothesize that such large scale motions occur as a rare event even under equilibrium conditions and that the interaction of such partially destabilized PrP(C)-conformers, which we named PrP(C*), contributes to the formation of pathogenic oligomeric species of the prion protein.

Animals↗

PubMed2005

AMBER force-field parameters for phosphorylated amino acids in different protonation states: phosphoserine, phosphothreonine, phosphotyrosine, and phosphohistidine.

We report a consistent set of AMBER force-field parameters for the most common phosphorylated amino acids, phosphoserine, phosphothreonine, phosphotyrosine, and phosphohistidine in different protonation states. The calculation of atomic charges followed the original restrained electrostatic potential fitting procedure used to determine the charges for the parm94/99 parameter set, taking alpha-helical and beta-strand conformations of the corresponding ACE-/NME-capped model peptide backbone into account. Missing force-field parameters were taken directly from the general AMBER force field (gaff) and the parm99 data set with minor modifications, or were newly generated based on ab initio calculations for model systems. Final parameters were validated by geometry optimizations and molecular-dynamics simulations. Template libraries for the phosphorylated amino acids in Leap format and corresponding frcmod parameter files are made available. [Figure: see text].

Acids↗

PubMed2003

AM1* parameters for phosphorus, sulfur and chlorine.

An extension of the AM1 semiempirical molecular orbital technique, AM1*, is introduced. AM1* uses AM1 parameters and theory unchanged for the elements H, C, N, O and F. The elements P, S and Cl have been reparameterized using an additional set of d orbitals in the basis set and with two-center core-core parameters, rather than the Gaussian functions used to modify the core-core potential in AM1. Voityuk and Rösch's AM1(d) parameters have been adopted unchanged for AM1* with the exception that new core-core parameters are defined for Mo-P, Mo-S and Mo-Cl interactions. Thus, AM1* gives identical results to AM1 for compounds with only H, C, N, O, and F, AM1(d) for compounds containing Mo, H, C, N, O and F only, but differs for molybdenum compounds containing P, S or Cl. The performance and typical errors of AM1* are discussed.

Chlorine↗

PubMed2003

Local molecular properties and their use in predicting reactivity.

Expressions for the local electron affinity, electronegativity and hardness are derived in analogy to the local ionization energy introduced by Sjoberg, Murray and Politzer. The local polarizability is also defined based on an additive atomic orbital polarizability model that uses Rivail's variational technique. The characteristics of these local properties at molecular surfaces and their relevance to electrophilic aromatic substitution, to S(N)2 reactivity and to the nucleophilicity of enolate ions are discussed.

Bromine↗

PubMed2003

Does metal ion complexation make radical clocks run fast?

Ab initio molecular orbital and density functional calculations at the CBS-RAD(QCISD,B3-LYP) level for Li+ and at B3LYP for Na+, K+, Cu+,and Ag+ reveal that the barrier to ring-closure of the 1-hexen-6-yl ("Delta(5)-hexenyl") radical to the cyclopentylmethyl radical, a so-called radical clock reaction, is decreased very significantly by complexation of the double bond to metal cations. This barrier lowering should occur on complexation with many metal ions, as shown by calculations on all of the monovalent ions listed above. Additional density functional calculations including explicit solvation of the model system complexed to the lithium ion with tetrahydrofuran suggest that the effect found is not limited to the gas phase but may also be significant in experimental radical clock reactions in solution, even for lithium.

Journal Article↗

PubMed2003

The structure and stability of Si60 and Ge60 cages: a computational study.

Structural studies of fullerene-like Si(60) and Ge(60) cages using ab initio methods were augmented by density functional tight-binding molecular dynamics (DFTB-MD) simulations of finite temperature effects. Neither the perfect I(h) symmetry nor the distorted T(h) structures are true minima. The energies of both are high relative to distorted, lower symmetry minima, C(i) and T, respectively, which still preserve C(60)-type connectivity. Both Si(60) and Ge(60) favor C(i) symmetry cages in which Si and Ge vertexes exhibit either near-trigonal or pyramidal geometries. These structural variations imply significant reactivity differences between different positions. The small magnetic shielding effects (NICS) indicate that aromaticity is not important in these systems. The inorganic fullerene cages have lower stabilities compared with their carbon analogs. Si(60) is stable towards spontaneous disintegration up to 700 K according to DFTB-MD simulations, and thus has potential for experimental observation. In contrast, Ge(60) preserves its cage structure only up to 200 K.

Journal Article↗