Buckling of stiff polymer rings in weak spherical confinement

Confinement is a versatile and well-established tool to study the properties of polymers either to understand biological processes or to develop new nanobiomaterials. We investigate the conformations of a semiflexible polymer ring in weak spherical confinement imposed by an impenetrable shell. We develop an analytic argument for the dominating polymer trajectory depending on polymer flexibility considering elastic and entropic contributions. Monte Carlo simulations are performed to assess polymer ring conformations in probability densities and by the shape measures asphericity and nature of asphericity. Comparison of the analytic argument with the mean asphericity and the mean nature of asphericity confirm our reasoning to explain polymer ring conformations in the stiff regime, where elastic response prevails

Confinement induces conformational transition of semiflexible polymer rings to figure eight form

Employing Monte Carlo simulations of semiflexible polymer rings in weak spherical confinement a conformational transition to figure eight shaped, writhed configurations is discovered and quantified.Comment: 6 pages, 5 figure

Illustration of the RP-REMD-Dock approach.

<p>(A) Based on the accessible surface of the two isolated partner molecules two surface groups of atoms are defined. The 1/d^-12 weighted distance is mainly determined by the closest contacts between the two groups and is used to define biasing penalty potentials for each replica (illustrated in B). The harmonic potentials allow for each replica a range of closest distances between the two partners such that the lower replicas allow close contacts without penalty but the higher replicas penalize such contacts by a quadratic function and push the partners on average slightly away from each other. The actual quadratic biasing potential in each replica run is illustrated in red (bold line), the range of potentials is indicated a thin lines. Since the allowed distance intervals overlap significantly between neighboring replicas a high acceptance rate for Hamiltonian replica exchanges leads to quick exploration of the biomolecular surfaces (replica scheme in the right panel).</p

Accelerated flexible protein-ligand docking using Hamiltonian replica exchange with a repulsive biasing potential

<div><p>A molecular dynamics replica exchange based method has been developed that allows rapid identification of putative ligand binding sites on the surface of biomolecules. The approach employs a set of ambiguity restraints in replica simulations between receptor and ligand that allow close contacts in the reference replica but promotes transient dissociation in higher replicas. This avoids long-lived trapping of the ligand or partner proteins at nonspecific, sticky, sites on the receptor molecule and results in accelerated exploration of the possible binding regions. In contrast to common docking methods that require knowledge of the binding site, exclude solvent and often keep parts of receptor and ligand rigid the approach allows for full flexibility of binding partners. Application to peptide-protein, protein-protein and a drug-receptor system indicate rapid sampling of near-native binding regions even in case of starting far away from the native binding site outperforming continuous MD simulations. An application on a DNA minor groove binding ligand in complex with DNA demonstrates that it can also be used in explicit solvent simulations.</p></div

The artificial “homeodomain” test case consists of a single ligand helix (light blue cartoon) that corresponds to the third helix of 3^rdhomeodomain from human homeoz protein (pdb2sy9) whereas the receptor was formed by the remaining helix 1 and 2 segments (dark blue cartoon).

<p>The loop segment between helix 2 and helix 3 in the original structure was eliminated to yield a complex of two peptide molecules. For the MD simulations the ligand helix was initially placed on the opposite site of the native placement and snapshots of sampled states after 20, 200, 800 and 1500 ps are indicated (red cartoon). The upper panels indicate snapshots obtained during regular MD simulation. Lower panels are snapshots found in the RP-REMD-Dock reference replica. At the final stage sampling (last panel on the right) several of the sampled configurations overlap with the native placement of the helix 3 ligand as found in the original homeodomain structure.</p

Fraction of near-native FKBP51-FK506 geometries obtained in RP-REMD-DOCK and MD simulations.

<p>Fraction of near-native FKBP51-FK506 geometries obtained in RP-REMD-DOCK and MD simulations.</p

Fraction of near-native protein-protein geometries obtained for the pdb2oo9-homodimer in RP-REMD-DOCK and MD simulations.

<p>Fraction of near-native protein-protein geometries obtained for the pdb2oo9-homodimer in RP-REMD-DOCK and MD simulations.</p