Conformational Sampling of Peptides in Cellular Environments

Abstract

Biological systems provide a complex environment that can be understood in terms of its dielectric properties. High concentrations of macromolecules and cosolvents effectively reduce the dielectric constant of cellular environments, thereby affecting the conformational sampling of biomolecules. To examine this effect in more detail, the conformational preference of alanine dipeptide, poly-alanine, and melittin in different dielectric environments is studied with computer simulations based on recently developed generalized Born methodology. Results from these simulations suggest that extended conformations are favored over alpha-helical conformations at the dipeptide level at and below dielectric constants of 5-10. Furthermore, lower-dielectric environments begin to significantly stabilize helical structures in poly-alanine at epsilon = 20. In the more complex peptide melittin, different dielectric environments shift the equilibrium between two main conformations: a nearly fully extended helix that is most stable in low dielectrics and a compact, V-shaped conformation consisting of two helices that is preferred in higher dielectric environments. An additional conformation is only found to be significantly populated at intermediate dielectric constants. Good agreement with previous studies of different peptides in specific, less-polar solvent environments, suggest that helix stabilization and shifts in conformational preferences in such environments are primarily due to a reduced dielectric environment rather than specific molecular details. The findings presented here make predictions of how peptide sampling may be altered in dense cellular environments with reduced dielectric response.

Biomolecular interactions modulate macromolecular structure and dynamics in atomistic model of a bacterial cytoplasm

“…Such a model would require in excess of 10 (Tanizaki et al, 2008) particles at an atomistic level of detail. As additional experimental data becomes available and computer platforms continue to increase in scale, this may become possible in the foreseeable future.…”

“…Metabolites add about 10 g/L (Bennett et al, 2009). Volume exclusion upon crowding favors compact macromolecular states (Minton, 2001), but the full physicochemical nature of cellular environments with attractive and repulsive interactions, solvation effects and co-solvents apparently leads to more varied effects (Monteith et al, 2015; Harada et al, 2013, 2012; Feig and Sugita, 2012; Kim and Mittal, 2013; Tanizaki et al, 2008). The key question is whether and how the in vivo behavior of biological macromolecules differs from their well-characterized in vitro properties.…”

Effects of background anionic compounds on the activity of the hammerhead ribozyme in Mg2+-unsaturated solutions

“…Based on the polyelectrolyte theory, it can be speculated that the interphosphate distances of single strands, which are more flexible than a duplex, are shortened when more Mg 2+ ions bind in the PEG-containing solution that have a decreased dielectric constant (Scheme 2). Because the media of intact cells and T7 bacteriophage particles have low dielectric constant values of about 50 or even much less [48][49][50], our results facilitate better understanding of ion binding to RNA under conditions mimicking the intracellular environment.…”

Crowding in Cellular Environments at an Atomistic Level from Computer Simulations

“…Such models can at least at a general qualitative level capture the main features of biomolecular structure and dynamics cellular environments. 149,168,169 Atomistic simulations, with explicit 26,143,170−176 or implicit solvent, 27,97,98 or multiscale models, where atomistic and coarse-grained resolutions are mixed, 169 provide even greater levels of detail and can, at least in principle, satisfy all of the requirements for modeling crowded cellular environments outlined above. However, because the balance between molecular stability, weak interactions, and solvent interactions in crowded environments depends on subtle shifts between enthalpic and entropic energy terms, the major challenge is an accurate interaction potential, both at the coarse-grained and atomistic level that can accurately reproduce both intra- and intermolecular interactions.…”