Symmetry-Directed Self-Organization in Peptide Nanoassemblies through Aromatic π–π Interactions

Almost all biological systems are assemblies of one or more biomolecules from nano- to macrodimensions. Unlike inorganic molecules, peptide systems attune with the conceptual framework of aggregation models when forming nanoassemblies. Three significant recent theoretical models have indicated that nucleation, end-to-end association, and geometry of growth are determined primarily by the size and electrostatics of the individual basic building blocks. In this study, we tested six model systems, differentially modulating the prominence of three design variables, namely, aromatic π–π interactions, local electrostatics, and overall symmetry of the basic building unit. Our results indicate that the crucial design elements in a peptide-based nanoassembly are (a) a stable extended π–π interaction network, (b) size, and (c) overall symmetry of the basic building blocks. The six model systems represent all of the design variables in the best manner possible, considering the complexity of a biomolecule. The results provide important directives in deciding the morphology and crystallinity of peptide nanoassemblies

Mapping the Geometric Evolution of Protein Folding Motor

<div><p>Polypeptide chain has an invariant main-chain and a variant side-chain sequence. How the side-chain sequence determines fold in terms of its chemical constitution has been scrutinized extensively and verified periodically. However, a focussed investigation on the directive effect of side-chain geometry may provide important insights supplementing existing algorithms in mapping the geometrical evolution of protein chains and its structural preferences. Geometrically, folding of protein structure may be envisaged as the evolution of its geometric variables: ϕ, and ψ dihedral angles of polypeptide main-chain directed by χ₁, and χ₂ of side chain. In this work, protein molecule is metaphorically modelled as a machine with 4 rotors ϕ, ψ, χ₁ and χ₂, with its evolution to the functional fold is directed by combinations of its rotor directions. We observe that differential rotor motions lead to different secondary structure formations and the combinatorial pattern is unique and consistent for particular secondary structure type. Further, we found that combination of rotor geometries of each amino acid is unique which partly explains how different amino acid sequence combinations have unique structural evolution and functional adaptation. Quantification of these amino acid rotor preferences, resulted in the generation of 3 substitution matrices, which later on plugged in the BLAST tool, for evaluating their efficiency in aligning sequences. We have employed BLOSUM62 and PAM30 as standard for primary evaluation. Generation of substitution matrices is a logical extension of the conceptual framework we attempted to build during the development of this work. Optimization of matrices following the conventional routines and possible application with biologically relevant data sets are beyond the scope of this manuscript, though it is a part of the larger project design.</p></div

MIDMAT 1 substitution matrix.

<p>MIDMAT 1 substitution matrix values are calculated based on basin statistics derived from the rotor combinations of amino acids in the structural dataset of 22,997 non-redundant structures from PISCES server. The amino acids are represented as their single letter codes.</p

MIDMAT 3 substitution matrix.

<p>MIDMAT3 substitution matrix constructed by following the third strategy (results section) for calculation of B_i, from the identical data set of 22,997 non-redundant structures from PISCES server.</p

Similar and unique hits for MIDMATs compared to BLOSUM62 and PAM30: The number of total, common and unique hits scored by MIDMATs (MIDMAT 1, MIDMAT 2 and MIDMAT 3), against BLOSUM62 and PAM30 matrices when plugged into a BLAST program against PDB, using the CASP11 database as a query set, while maintaining the default parameters of BLAST.

Similar and unique hits for MIDMATs compared to BLOSUM62 and PAM30: The number of total, common and unique hits scored by MIDMATs (MIDMAT 1, MIDMAT 2 and MIDMAT 3), against BLOSUM62 and PAM30 matrices when plugged into a BLAST program against PDB, using the CASP11 database as a query set, while maintaining the default parameters of BLAST.</p

Mapping the Geometric Evolution of Protein Folding Motor - Fig 1

Functional rotors involved in structure formation: a) The four rotors representing four dihedral angles of an amino acid residue in a polypeptide chain. b) Orientation of four rotor motions during formation and breaking of helix and sheet with positive sign indicating right handed or clockwise direction and negative sign indicating left handed or counter clockwise direction. c) Rotational patterns of rotors during helix formation (green) and helix breaking (red) are shown d) Orientation of rotors resulting in the formation and breaking of sheeted structures.</p

Formation of extended sheeted structures and their breaking.

<p>S-3 to S basin shifts indicates formation of sheet as a result of right handed movement of the χ₁ rotor and complimenting counter rotation of ϕ; ψ rotor moves in the counter-direction of the ϕ rotor throughout formation and breaking of sheet. See also Figures A1-A4 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0163993#pone.0163993.s001" target="_blank">S1 File</a>.</p

Differential distribution of side-chain and main-chain rotors among representative amino acid sets.

<p>Dissimilar ϕ vs χ₁ basins in protein structures for various amino acid types. Differential basin preferences for different amino-acids are calculated from the entire database of 22,977 non-redundant structures. Localization for the χ₁ and ϕ dihedral rotors in protein structures are evident.</p

MIDMAT 2 substitution matrix.

<p>MIDMAT 2 substitution matrix constructed using a different approach than MIDMAT1 as discussed in results section, from the same set of 22,997 non-redundant structures from PISCES server. The amino acids are represented as single letter codes.</p

Helical structure formation and its breaking.

<p>H-3 to H basin shifts indicate formation of helix as a result of left handed rotation of the χ₁ rotor and right handed rotation of ϕ by 80° while helix breaking the rotors assume reverse orientations. The ψ rotor maintains its right handed rotation throughout helix formation and breaking. See also Figures A1-A4 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0163993#pone.0163993.s001" target="_blank">S1 File</a>.</p