Free-energy landscapes and insertion pathways for peptides in membrane environment.

Free-energy landscapes for short peptides-specifically for variants of the pH low insertion peptide (pHLIP)-in the heterogeneous environment of a lipid bilayer or cell membrane are constructed, taking into account a set of dominant interactions and the conformational preferences of the peptide backbone. Our methodology interprets broken internal H-bonds along the backbone of a polypeptide as statistically interacting quasiparticles, activated from the helix reference state. The favored conformation depends on the local environment (ranging from polar to nonpolar), specifically on the availability of external H-bonds (with H_{2}O molecules or lipid headgroups) to replace internal H-bonds. The dominant side-chain contribution is accounted for by residue-specific transfer free energies between polar and nonpolar environments. The free-energy landscape is sensitive to the level of pH in the aqueous environment surrounding the membrane. For high pH, we identify pathways of descending free energy that suggest a coexistence of membrane-adsorbed peptides with peptides in solution. A drop in pH raises the degree of protonation of negatively charged residues and thus increases the hydrophobicity of peptide segments near the C terminus. For low pH, we identify insertion pathways between the membrane-adsorbed state and a stable trans-membrane state with the C terminus having crossed the membrane.

Mechanical response to tension and torque of molecular chains via statistically interacting particles associated with extension, contraction, twist, and supercoiling.

A methodology for the statistical mechanical analysis of polymeric chains under tension introduced previously is extended to include torque. The response of individual bonds between monomers or of entire groups of monomers to a combination of tension and torque involves, in the framework of this method of analysis, the (thermal or mechanical) activation of a specific mix of statistically interacting particles carrying quanta of extension or contraction and quanta of twist or supercoiling. The methodology, which is elucidated in applications of increasing complexity, is capable of describing the conversion between twist chirality and plectonemic chirality in quasistatic processes. The control variables are force or extension and torque or linkage (a combination of twist and writhe). The versatility of this approach is demonstrated in two applications relevant and promising for double-stranded DNA under controlled tension and torque. One application describes conformational transformations between (native) B-DNA, (underwound) S-DNA, and (overwound) P-DNA in accord with experimental data. The other application describes how the conversion between a twisted chain and a supercoiled chain accommodates variations of linkage and excess length in a buckling transition.

Molecular chains under tension: Thermal and mechanical activation of statistically interacting extension and contraction particles.

This work introduces a methodology for the statistical mechanical analysis of polymeric chains under tension controlled by optical or magnetic tweezers at thermal equilibrium with an embedding fluid medium. The response of single bonds between monomers or of entire groups of monomers to tension is governed by the activation of statistically interacting particles representing quanta of extension or contraction. This method of analysis is capable of describing thermal unbending of the freely jointed or wormlike chain kind, linear or nonlinear contour elasticity, and structural transformations including effects of cooperativity. The versatility of this approach is demonstrated in an application to double-stranded DNA undergoing torsionally unconstrained stretching across three regimes of mechanical response including an overstretching transition. The three-regime force-extension characteristic, derived from a single free-energy expression, accurately matches empirical evidence.