A Molecular-Dynamics Simulation Study of the Conformational Preferences of Oligo(3-hydroxyalkanoic acids) in Chloroform Solution

Abstract

The GROMOS96 molecular-dynamics (MD) program and force field was used to calculate the conformations at 298 K in CHCl 3 solution of two hexakis(3-hydroxyalkanoic acids). One consists of (R)-3-hydroxybutanoate (HB) residues only: HÀ(OCH(Me)ÀCH 2 ÀCO) 6 ÀOH (1). The other one carries the side chains of valine, alanine, and leucine: HÀ(OCH(CHMe 2 )CH 2 ÀCOÀOÀCH(Me)ÀCH 2 ÀCOÀOÀCH(CH 2 CHMe 2 )ÀCH 2 ÀCO) 2 ÀOH (2), with homochiral 3-hydroxyalkanoate (HA) moieties. In both cases, the conformational equilibria were sampled 2500 times for 25 ns. Other than clusters of arrangements with interresidual hydrogen bonding (between the O-and C-terminal OH and COOH groups, and with chain-bound ester carbonyl O-atoms; Fig. 6), there are no preferred backbone conformations in which the molecules 1 and 2 spend more than 5% of the time. Specifically, neither the 2 1 -nor the 3 1 -helical conformation of the oligoester backbone (found in stretched fibers, in lamellar crystallites, and in single crystals of polymers PHB and of oligomers OHB) is sampled to any significant extent ( Fig. 8 and 9), in spite of the high population, in both oligomers, of the (À)-synclinal conformation around the C(2)ÀC (3) bond (angle f 2 in Fig. 2). In contrast to b-oligopeptides, for which strongly preferred secondary structures are found after a few ns, and for which the number of conformations levels off with time, the number of conformational clusters of the corresponding oligoesters found by our force-field MD calculations increases steadily over the observation time of 25 ns (Fig. 5). Thus, the conclusion from biological and physical-chemical studies, according to which the PHB chain is extremely flexible, is confirmed by our computational investigation: in CHCl 3 solution, the hexakis(3-hydroxyalkanoate) chain samples its conformational space randomly! 1. Introduction. ± Associated with the biological role of the short-chain poly[(R)-3-hydroxybutanoate] (PHB) [1], which has been shown to allow the passage of ions across phospholipid bilayer membranes under voltage-driven and concentration-driven conditions [2], or to function as a transmembrane ion-channel when associated with Ca polyphosphate [1 ± 3], is the question of its secondary structure. From the investigation of PHB or PHB derivatives in the solid state, two different folding patterns were recognized: a 2 1 helix in stretched fibers [4] and in lamellar crystallites of the polymer

Polyhydroxybutyrate Targets Mammalian Mitochondria and Increases Permeability of Plasmalemmal and Mitochondrial Membranes

“…Although the exact molecular mechanisms of such transport are currently unknown, we note that a polyester structure is able to provide the conformation which will permit such transport. Indeed, PHB is a polymer composed of many alternating hydrophobic and hydrophilic groups [2], [18]. This polymer can form complexes with metal ions and fold with the hydrophobic groups facing the hydrophobic environment found in the lipid bilayer.…”

The Role of Short-Chain Conjugated Poly-(R)-3-Hydroxybutyrate (cPHB) in Protein Folding

“…Moreover, polyesters such as PHB, in contrast to polyamides and polypeptides, have highly flexible backbone structures, since they lack the stabilizing element of internal hydrogen bonds and the rigidity of a peptide bond. The extremely high flexibility of the PHB backbone at physiological temperatures has been amply demonstrated by Seebach et al , using circular dichroism and fluorescence (FRET) measurements [31], nuclear magnetic resonance (NMR) spectroscopy [32,33] and molecular dynamics simulations [34]. However, it is important to note that the glass temperature of PHB is ~10 °C, so that the PHB backbone becomes increasingly more rigid as temperatures are lowered below the physiological range.…”

Synthesis and NMR Analysis in Solution of Oligo(3-hydroxyalkanoic acid) Derivatives with the Side Chains of Alanine, Valine, and Leucine (β-Depsides): Coming Full Circle from PHB toβ-Peptides to PHB

“…The conformation about the angle f 2 of all the units of 3 deviates from that found in linear PHB derivatives [17], indicating that the side-chain modifications have indeed altered the backbone conformation, but our going full circle from PHB to b-peptides to PHB has not led to the discovery of a predominant secondary structure! In a series of four papers, including the present one, we have now established the extremely high conformational flexibility of the polyester backbone in PHB [17] [21] [37]. A preferred conformation of oligo(3-hydroxybutyrates) in homogeneous solution could be detected neither by state-of-the-art NMR spectroscopy with isotopically [17] or structurally (the present paper) labeled, nor by FRET measurements [21] with fluorescence-labeled OHBs, nor by GROMOS96 moleculardynamics simulations of the hexamers 1 (n 1) and 3 11 ).…”