Universal geometrical factor of protein conformations as a consequence of energy minimization

The biological activity and functional specificity of proteins depend on their native three-dimensional structures determined by inter- and intra-molecular interactions. In this paper, we investigate the geometrical factor of protein conformation as a consequence of energy minimization in protein folding. Folding simulations of 10 polypeptides with chain length ranging from 183 to 548 residues manifest that the dimensionless ratio (V/(A)) of the van der Waals volume V to the surface area A and average atomic radius of the folded structures, calculated with atomic radii setting used in SMMP [Eisenmenger F., et. al., Comput. Phys. Commun., 138 (2001) 192], approach 0.49 quickly during the course of energy minimization. A large scale analysis of protein structures show that the ratio for real and well-designed proteins is universal and equal to 0.491\pm0.005. The fractional composition of hydrophobic and hydrophilic residues does not affect the ratio substantially. The ratio also holds for intrinsically disordered proteins, while it ceases to be universal for polypeptides with bad folding properties.Comment: 6 pages, 1 table, 4 figure

Modelling the unfolding pathway of biomolecules: theoretical approach and experimental prospect

We analyse the unfolding pathway of biomolecules comprising several independent modules in pulling experiments. In a recently proposed model, a critical velocity $v_{c}$ has been predicted, such that for pulling speeds $v>v_{c}$ it is the module at the pulled end that opens first, whereas for $v<v_{c}$ it is the weakest. Here, we introduce a variant of the model that is closer to the experimental setup, and discuss the robustness of the emergence of the critical velocity and of its dependence on the model parameters. We also propose a possible experiment to test the theoretical predictions of the model, which seems feasible with state-of-art molecular engineering techniques.Comment: Accepted contribution for the Springer Book "Coupled Mathematical Models for Physical and Biological Nanoscale Systems and Their Applications" (proceedings of the BIRS CMM16 Workshop held in Banff, Canada, August 2016), 16 pages, 6 figure

Mechanical unfolding of DDFLN4 studied by coarse-grained knowledge-based CABS model

Mechanical unfolding of the fourth domain of Distyostelium discoideum filamin ( DDFLN 4) was studied using a CABS – coarse-grained knowledge-based protein model. Our study demonstrates that CABS is capable of reproducing the unfolding free energy landscape of protein unfolding and highlights an important role of non-native interactions in the protein unfolding process. The obtained three peaks in the force-extension profile suggest a four-state picture of DDFLN 4 protein unfolding and correspond reasonably to the results of the all-atom simulation in explicit solvent

Coarse-grained modeling of protein structure, dynamics and protein-protein interactions

Theoretical prediction of protein structures and dynamics is essential for understanding the molecular basis of drug action, metabolic and signaling pathways in living cells, designing new technologies in the life science and material sciences . We developed and validated a novel multiscale methodology for the study of protein folding processes including flexible docking of proteins and peptides. The new modeling technique starts from coarse-grained large-scale simulations, followed by selection of the most plausible final structures and intermediates and, finally, by an all-atom rectification of the obtained structures. Except for the most basic bioinformatics tools, the entire computational methodology is based on the models and algorithms developed in our lab. The coarse-grained simulations are based on a high-resolution lattice representation of protein structures, a knowledge based statistical force field and efficient Monte Carlo dynamics schemes, including Replica Exchange algorithms. This paper focuses on the description of the coarse-grained CABS model and its selected applications

Chameleonicity and folding of the C-fragment of TOP7

Using a specifically designed Go-model we have performed all-atom simulations of the C-fragment of TOP7. Our results support previous results (see Mohanty S. et al., Proc. Natl. Acad. Sci. U.S.A., 105 (2008) 8004; Mohanty S. and Hansmann U. H. E., J. Phys. Chem. B, 112 (2008) 15134) that indicate folding of this protein through configurations with non-native secondary structure. The N-terminal residues form first an extension of a subsequent α-helix, before finally refolding into a β-strand that completes a three-stranded β-sheet in the final structure. We show that mutations which reduce the “chameleonicity” of N-terminal residues (by increasing the propensity for “strandness” and reducing that for “helicity”) lead to folding into the same structure but with reduced folding rates and larger free-energy barriers

Key factors governing fibril formation of proteins: insights from simulations and experiments

Fibril formation of proteins and peptides is associated with a large group of major human diseases, including Alzheimer’s disease, prion disorders, amyotrophic lateral sclerosis, type 2 diabetes, etc. Therefore, understanding the key factors that govern this process is of paramount importance. The fibrillogenesis of polypeptide chains depends on their intrinsic properties as well as on the external conditions. In this mini-review we discuss the relationship between fibril formation kinetics and the sequence, aromaticity, hydrophobicity, charge and population of the so called fibril-prone conformation in a monomer state. The higher the population, the faster is the fibril elongation and this dependence may be described by a single exponential function. This observation opens up a new way to understand the fibrillogenesis of bio-molecules at the monomer level. We will also discuss the influence of the environment with focus on the recently observed dual effect of crowders on the aggregation rat es of polypeptide chains