Biology subjects

Srebnik, S.

Publications and source records attributed to Srebnik, S..

5 recordsLinked to original sources

bioRxiv2025

Advanced coarse-grained model for fast simulation of nascent polypeptide chain dynamics within the ribosome

The nascent polypeptide exit tunnel (NPET) is a sub-compartment of the ribosome that constrains the dynamics of nascent polypeptide chains during protein translation. Simulating these dynamics has been limited due by the spatial scale of the ribosome and the temporal scale of elongation. Here, we present an automated pipeline to extract the geometry of the NPET and the ribosome surface at high resolution from any ribosome structure. We further convert this into a coarse-grained (CG) bead model that can be used in molecular simulations. This CG model more accurately captures NPET geometry than previous representations and allows for the simulation of co- and post-translational processes that are computationally prohibitive with all-atom approaches. In particular, we illustrate how the CG model may be used to simulate the elongation dynamics of the nascent polypeptide and its escape post-translation, as well as evaluate free energy landscapes and examine the influence of electrostatics on the nascent polypeptide escape. SIGNIFICANCEThe translation of nascent polypeptide chains is mediated by the ribosome, with interactions between the protein and the nascent polypeptide exit tunnel (NPET) impacting the process. However, modeling and simulating protein elongation and its escape from the NPET remain challenging due to computational limitations in spatial and temporal resolution. Here, we develop a computational pipeline for generating coarse-grained (CG) models of the NPET and ribosome surface from any ribosome structure that allow for both effective and accurate computer simulations. We demonstrate how the model can be implemented for various simulations, including the elongation dynamics of the nascent polypeptide and escape of the chain post-translation, as well as in estimating free energy landscapes and examining the impact of the charged environment on the escape time.

biophysics↗

bioRxiv2025

Detection of archaeal- and prokaryotic-like ribosome exit tunnels within eukaryotic kingdoms

The ribosome exit tunnel is a critical sub-compartment that actively regulates the folding and dynamics of nascent polypeptide chains during protein translation. In this study, we systematically examined tunnel structures of 725 ribosome models obtained through cryo-EM and X-ray crystallography, to quantify structural variations across different species and biological domains. Hierarchical clustering revealed significant geometric differences between prokaryotic and eukaryotic ribosomes, with a surprising discovery: six eukaryotic protist species display tunnel structures remarkably similar to those of archaea and bacteria. By analyzing the sequences and structures of ribosomal components forming the tunnel walls, we identified four specific sequence modifications in ribosomal proteins and ribosomal RNAs (rRNA) responsible for these unique geometric variations, and detected these modifications in additional protist species lacking existing 3D structural data. Overall, our findings highlights some complex evolutionary mechanisms governing ribosomal protein and large subunit rRNA, providing novel insights into the tunnels regulatory role in protein translation.

molecular biology↗

bioRxiv2022

Geometric differences in the ribosome exit tunnel impact the escape of small nascent proteins

The exit tunnel is the sub-compartment of the ribosome that contains the nascent polypeptide chain and as such, is involved in various vital functions, including regulation of translation and protein folding. As the geometry of the tunnel shows important differences across species, we focus on key geometrical features of eukaryote and prokaryote tunnels. We used a simple coarse-grained molecular dynamics model to study the role of the tunnel geometry in the post-translational escape of short proteins (sORFs), with lengths ranging from 6 to 56 amino acids. We found that the probability of escape for prokaryotes is one for all but the 12-mer chains. Moreover, proteins of this length have an extremely low escape probability in eukaryotes. A detailed examination of the associated single trajectories and energy profiles showed that these variations can be explained by the interplay between the protein configurational space and the confinement effects introduced by the constriction sites of the ribosome exit tunnel. For certain lengths, either one or both of the constriction sites can lead to the trapping of the protein in the "pocket" regions preceding these sites. As the distribution of existing sORFs indicate some bias in length that is consistent with our findings, we finally suggest that the constraints imposed by the tunnel geometry have impacted the evolution of sORFs.

biophysics↗

bioRxiv2017

Assessment of hydrophobicity scales for protein stability and folding using energy and RMSD criteria

De novo prediction of protein folding is an open scientific challenge. Many folding models and force fields have been developed, yet all face difficulties converging to native conformations. Hydrophobicity scales (HSs) play a crucial role in such simulations as they define the energetic interactions between protein residues, thus determining the energetically favorable conformation. While many HSs have been developed over the years using various methods, it is surprising that the scales show very weak consensus in their assignment of hydrophobicity indexes to the various residues. In this work, several HSs are systematically assessed via atomistic Monte Carlo simulation of folding of small proteins, by converting the HSs of interest into residue-residue contact energy matrices. HSs that poorly preserve native structures of proteins were tuned by applying a linear transformation. Subsequently, folding simulations were used to examine the ability of the HSs to correctly fold the proteins from a random initial conformation. Root mean square deviation (RMSD) and energy of the proteins during folding were sampled and used to define an ER-score, as the correlation between the 2-dimensional energy-RMSD (ER) histogram with 50% lowest energy conformations and the ER histogram with 50% lowest RMSD conformations. Thus, we were able to compare the ability of the different HSs to predict de novo protein folding quantitatively.

biophysics↗

bioRxiv2017

The Relation Between α-Helical Conformation and Amyloidogenicity

Amyloid fibrils are stable aggregates of misfolded proteins and polypeptides that are insoluble and resistant to protease activity. Abnormal formation of amyloid fibrils in vivo may lead to neurodegenerative disorders and other systemic amyloidosis such as Alzheimers, Parkinsons, and atherosclerosis. Because of their clinical importance amyloids are found under intense scientific research. Amyloidogenic sequences of short polypeptide segments within proteins are responsible for the transformation of correctly folded proteins into parts of larger amyloid fibrils. The -helical secondary structure is believed to host many amyloidogenic sequences and be a key player in different stages of the amyloidogenesis process. Most of the studies on amyloids focus on the role of amyloidogenic sequences. The focus of this study is the relation between amyloidogenicity and the structure of the amyloidogenic -helical sequence. We have previously shown that the -helical conformation may be expressed by two parameters ({theta} and{rho} ) that form orthogonal coordinates based on the Ramachandran dihedrals ({varphi} and{psi} ) and provide an illuminating interpretation of the -helical conformation. By performing statistical analysis on -helical conformations found in the protein data bank, an apparent relation between -helical conformation, as expressed by{theta} and{rho} , and amyloidogenicity is revealed. Remarkably, random amino acid sequences, whose helical structure was obtained from the most probably dihedral angles as obtained from PDB data, revealed the same dependency of amyloidogenicity, suggesting the importance of -helical structure as opposed to sequence.

biophysics↗