Toward Ab Initio Protein Folding: Inherent Secondary Structure Propensity of Short Peptides from the Bioinformatics and Quantum-Chemical Perspective

Abstract

By combining bioinformatics with quantumchemical calculations, we attempt to address quantitatively some of the physical principles underlying protein folding. The former allowed us to identify tripeptide sequences in existing protein three-dimensional structures with a strong preference for either helical or extended structure. The selected representatives of pro-helical and pro-extended sequences were converted into "isolated" tripeptidescapped at N-and C-terminiand these were subjected to an extensive conformational sampling and geometry optimization (typically thousands to tens of thousands of conformers for each tripeptide). For each conformer, the QM(DFT-D3)/ COSMO-RS free-energy value was then calculated, G conf (solv). The ΔG conf (solv) is expected to provide an objective, unbiased, and quantitatively accurate measure of the conformational preference of the particular tripeptide sequence. It has been shown that irrespective of the helical vs extended preferences of the selected tripeptide sequences in context of the protein, most of the low-energy conformers of isolated tripeptides prefer the R-helical structure. Nevertheless, pro-helical tripeptides show slightly stronger helix preference than their pro-extended counterparts. Furthermore, when the sampling is repeated in the presence of a partner tripeptide to mimic the situation in a β-sheet, pro-extended tripeptides (exemplified by the VIV) show a larger free-energy benefit than pro-helical tripeptides (exemplified by the EAM). This effect is even more pronounced in a hydrophobic solvent, which mimics the less polar parts of a protein. This is in line with our bioinformatic results showing that the majority of pro-extended tripeptides are hydrophobic. The preference for a specific secondary structure by the studied tripeptides is thus governed by the plasticity to adopt to its environment. In addition, we show that most of the "naturally occurring" conformations of tripeptide sequences, i.e., those found in existing three-dimensional protein structures, are within ∼10 kcal•mol −1 from their global minima. In summary, our "ab initio" data suggest that complex protein structures may start to emerge already at the level of their small oligopeptidic units, which is in line with a hierarchical nature of protein folding.

Residue Folding Degree—Relationship to Secondary Structure Categories and Use as Collective Variable

“…We would like to declare upfront that we do not intend/propose to use the residue folding degree as a substitute for SS defining algorithms. The dynamical aspects of stabilising effects of proteins SS are studied elsewhere [ 52 , 53 , 54 ].…”

Thiazole–amino acids: influence of thiazole ring on conformational properties of amino acid residues

“…On the contrary, the backbone-based theory postulates that the universality of the osmolyte effect points to the conclusion that self-organisation takes place mainly in the main chain (Rose et al 2006 ; Dill et al 2008 ). A recent ab initio study confirmed that such a small unit as tripeptides fragments composed of standard amino acids already exhibit a small tendency to adopt a particular secondary structure (helical or extended) (Culka et al 2019 ). Regardless of the chosen theory, it is sure that the conformational preferences of amino acid residues or short peptide fragments have a high impact on the overall secondary structure.…”

“…The capability of changing ligand conformation to improve binding affinity in proteins is one of the biomolecular engineering tools crucial for drug discovery and design (Lassila 2010 ; Gagné et al 2012 ; Boehr et al 2018 ; Ding et al 2020 ; Aguesseau-Kondrotas et al 2019 ). Mapping the conformational space of small peptide fragments is also an important prerequisite in decoding the protein folding process and understanding protein structure (Culka et al 2019 ; Culka and Rulíšek 2019 , 2020 ; Ganesan and Paranthaman 2020 ; Chahkandi et al 2014 ). According to the funnel landscape theory, the side chains are primarily responsible for folding diversity.…”

Fast and accurate quantum mechanical modeling of large molecular systems using small basis set Hartree–Fock methods corrected with atom-centered potentials

“…This choice of training set properties is justified by the potential target applications of small basis set HF based methods, namely fast geometry optimizations and non-covalent interaction strengths in large systems as well as high-throughput 87 screening of conformers in combination with conformer search techniques [88][89][90] . These applications are useful, for instance, when performing exhaustive conformational searches of macrocyclic drugs [91][92][93][94][95][96] and other pharmaceutical candidates 97 , and studying biochemical processes like protein folding [98][99][100] and puckering of nucleotides 101,102 .…”