Synthesis,biological studies and molecular dynamics of new anticancer RGD-based peptide conjugates for targeted drug delivery

New cyclic RGD peptide-anticancer agent conjugates, with different chemical functionalities attached to the parent peptide were synthesized in order to evaluate their biological activities and to provide a comparative study of their drug release profiles. The Integrin binding c(RGDfK) penta-peptide was used for the synthesis of Camptothecin (CPT) carbamate and Chlorambucil (CLB) amide conjugates. Substitution of the amino acid Lys with Ser resulted in a modified c(RGDfS) with a new attachment site, which enabled the synthesis of an ester CLB conjugate. Functional versatility of the conjugates was reflected in the variability of their drug release profiles, while the conserved RGD sequence of a selective binding to the α_v integrin family, likely preserved their recognition by the Integrin and consequently their favorable toxicity towards targeted cancer cells. This hypothesis was supported by a computational analysis suggesting that all conjugates occupy conformational spaces similar to that of the Integrin bound bio-active parent peptide.     

A molecular dynamics study of the stoichiometric complex formed by poly (alpha, L-glutamate) and octyltrimethylammonium ions in chloroform solution.

We present a molecular dynamics simulation at 300 K in explicit solvent environment of chloroform of the stoichiometric complex formed by poly(alpha,L-glutamate) and octyltrimethylammonium ions. We observed that the alpha-helix conformation of the polypeptide chain remains stable during a 2-ns run. The surfactant ions predominantly adopted an extended conformation that is stabilized by favorable interactions with the organic solvent. Analysis of the organization of the surfactant with respect to the polypeptide chain indicated that each octyltrimethylammonium cation was preferentially bound to more than one carboxylate group. It was found that the most populated arrangement was that with the surfactant cations interacting with two carboxylate groups simultaneously.     

Maintaining diversity in an artificially propagated population

Populations may suffer unexpected loss or distortion of biodiversity as a consequence of strategies employed in artificial propagation programs. The Trinity River Fish Hatchery may have inadvertently experienced this while attempting to preserve diversity in a return time within a Chinook salmon population. We develop a model for this system and prove that the long-term distribution of return types converges and that it is strongly tied to the management strategy. Given estimates of heritabilities for return type and differential survival rates, an estimate of this long-term distribution can be computed easily.     

Molecular Dynamics Simulation of the Fast Ion Conductor δ-Bi2O3. III. Ionic Motion

Dynamical aspects of molecular dynamics (MD) simulations are analysed with a view to determining the nature of fast-ion conduction in δ-Bi₂O₃. The ratio P _α of the moments of the self-correlation density distribution function, the velocity autocorrelation function (VAF), VAF integrals and VAF Fourier transforms, together with mean square displacement (MSD) data are interpreted in the light of experiment. It is shown that O^2- migration cannot adequately be described by either the hopping or liquid-like models of conduction but is best regarded as belonging to an intermediate category. Analysis of the fine structure of the P _α, MSD and VAF plots yields interesting correlations with vibrational modes.     

Molecular Dynamics Simulation Studies of Zeolite-A. IV. Structure and Dynamics of NH4 + ions in a Rigid Dehydrated Zeolite-A

Abstract

In recent papers [1–3] we reported molecular dynamics simulation studies of ions and water molecules adsorbed in a rigid zeolite-A framework using a simple Lennard-Jones potential plus Coulomb potential with Ewald summation to investigate the structure and dynamics of the adsorbates. In the present paper the same technique is applied to study the local structure and dynamics of NH₄ ⁺ ions in a rigid dehydrated zeolite-A. During the preliminary equilibration, the unstable NH₄(4) type ion (the 12th ion) is pushed down to near a more stable 6-ring position in the α-cage that is already associated with an NH₄(1) type ion (the 1st) in the β-cage, which moves to another 6-ring position in the β-cage that is already associated with an NH₄(2) type ion (the 7th) in the α-cage. Calculated x, y, and z coordinates of some NH₄ ⁺ ions are in good agreement with those obtained from an X-ray diffraction experiment except that no NH₄(4) type ion is found and there are six NH₄(2) type ions instead of 0.5 and 5.5 occupancy. The analyses of calculated interatomic distances and time correlation functions of these ions indicate that the NH₄(1 – 1) and NH₄(3) type ions are associated loosely with only one O (3) atom of the 6-ring and with only one O (1) atom of the 8-ring windows, respectively, while the NH₄(1–2) and NH₄(2) type ions are associated strongly with two or three O (3) atoms of the 6-ring windows in the α- and β-cages, respectively. The analysis of hydrogen bond time correlation functions of these ions indicate that about one, two or three, three, and one hydrogen bond of each NH₄(1–1), NH₄(1–2), NH₄(2) and NH₄(3) type ion is kept for 1.4, 21, 75, and 1.4 ps, respectively, before breakup of the hydrogen bond occurs and significant exchange of O atom hydrogen-bonded to the ion.     

Role of methyl groups in dynamics and evolution of biomolecules

Recent studies have discovered strong differences between the dynamics of nucleic acids (RNA and DNA) and proteins, especially at low hydration and low temperatures. This difference is caused primarily by dynamics of methyl groups that are abundant in proteins, but are absent or very rare in RNA and DNA. In this paper, we present a hypothesis regarding the role of methyl groups as intrinsic plasticizers in proteins and their evolutionary selection to facilitate protein dynamics and activity. We demonstrate the profound effect methyl groups have on protein dynamics relative to nucleic acid dynamics, and note the apparent correlation of methyl group content in protein classes and their need for molecular flexibility. Moreover, we note the fastest methyl groups of some enzymes appear around dynamical centers such as hinges or active sites. Methyl groups are also of tremendous importance from a hydrophobicity/folding/entropy perspective. These significant roles, however, complement our hypothesis rather than preclude the recognition of methyl groups in the dynamics and evolution of biomolecules.     

Plant litter feedback and population dynamics in an annual plant,<Emphasis Type="Italic"> Cardamine pensylvanica</Emphasis>

The presence of litter has the potential to alter the population dynamics of plants. In this paper, we explore the effects of litter on population dynamics using a simple experimental laboratory system with populations of the annual crucifer, Cardamine pensylvanica. Using a factorial experiment with four densities and three litter levels, we determined the effect of litter on biomass and plant fecundity, and the life stages responsible for these changes in yield. Although litter had significant effects on seed germination and on seedling survivorship, we show, using a population dynamics model, that these effects were not demographically significant. Rather, the potential effect of litter on population dynamics resulted almost entirely from its effect on biomass. Persistent litter suppressed plant biomass and apparently removed the direct density effect present in the absence of litter. Thus, litter changed the shape of the recruitment curve from slightly humped to asymptotic. In addition to changing the shape of the recruitment curve, litter reduced the carrying capacity of the populations. Thus, the population dynamics model indicated that not all statistically significant responses were dynamically significant. Given the potential complexity of litter effects, simple population models provide a powerful tool for understanding the potential consequences of short-term responses. Received: 8 September 1999 / Accepted: 5 April 2000