Peptide models have proved extremely valuable in probing the relationship between local sequence information and folded conformation in the absence of the tertiary interactions found in the native state of proteins, allowing intrinsic secondary structure propensities to be investigated in isolation. With this rationale in mind, we have chosen to investigate polymerizable motifs consisting of a beta-strand linked by a beta-turn sequence. Specifically, beta-strand domain represent sequences highly predisposed to assume double-stranded beta-sheet conformation, whereas beta-turn conformation is formed by short, bioactive peptides homologous of natural sequences. With the aim to design polymer with a strong tendency to adopt a specific compact conformation we have synthesized two "model" sequences: Boc-Pro-Phe-Ile-Leu-OMe Boc-Val-Phe-Ile-Leu-OMe Conformational analysis of these "models" using NMR spectroscopy permit us to evaluate steric interaction in isolation.
One remarkable characteristic of proteins is that side chains comprising the hydrophobic core are as closely packed as organic crystals. In most proteins with known 3D structure the core residues are rarely disordered and adopt one of a small number of alternative conformations. This almost unique packing is affected by a combination of steric interaction (excluded volume effects) and energetic stabilization (hydrophobic, polar and charge interactions). The proportion by which these interactions contribute to the overall stability is unknown but several studies suggest that steric and hydrophobic interactions are of primary importance. Upon folding to its native backbone topology the conformational space of a protein is cut by many orders of magnitude, due to excluded volume. At the level of a single torsion, the number of rotamer states is reduced by a factor of approximately 2. The native backbone can still accommodate many different side chains conformations, while maintaining its high degree of compactness. Other sources of stabilization ( attractive van der Waals interactions, hydrogen bonding, and polar interaction) are necessary to overcome the final entropic cost associated with fixing the side chains in their native conformation. To access the relative influence of hydrogen bonding and hydrophobic interactions on beta-structure formation one must be able to parse their contribution separately. Unfortunately, due to the inherent complexity of proteins, systematically altering global hydrophobicity through mutagenesis, without changing protein structure is an extraordinarily difficult task. This task can be made easier, however, employing a biopolymer rather than a fully structured protein.
Relative Influence of Steric Interactions and Energetic Stabilization on beta-Structure Formation
Emma Fenude;Michele Saviano
2017
Abstract
One remarkable characteristic of proteins is that side chains comprising the hydrophobic core are as closely packed as organic crystals. In most proteins with known 3D structure the core residues are rarely disordered and adopt one of a small number of alternative conformations. This almost unique packing is affected by a combination of steric interaction (excluded volume effects) and energetic stabilization (hydrophobic, polar and charge interactions). The proportion by which these interactions contribute to the overall stability is unknown but several studies suggest that steric and hydrophobic interactions are of primary importance. Upon folding to its native backbone topology the conformational space of a protein is cut by many orders of magnitude, due to excluded volume. At the level of a single torsion, the number of rotamer states is reduced by a factor of approximately 2. The native backbone can still accommodate many different side chains conformations, while maintaining its high degree of compactness. Other sources of stabilization ( attractive van der Waals interactions, hydrogen bonding, and polar interaction) are necessary to overcome the final entropic cost associated with fixing the side chains in their native conformation. To access the relative influence of hydrogen bonding and hydrophobic interactions on beta-structure formation one must be able to parse their contribution separately. Unfortunately, due to the inherent complexity of proteins, systematically altering global hydrophobicity through mutagenesis, without changing protein structure is an extraordinarily difficult task. This task can be made easier, however, employing a biopolymer rather than a fully structured protein.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
