Quantifying Nonnative Interactions in the Protein-Folding Free-Energy Landscape

Abstract

Protein folding is a central problem in biological physics. Energetic roughness is an important aspect that controls protein-folding stability and kinetics. The roughness is associated with conflicting interactions in the protein and is also known as frustration. Recent studies indicate that an addition of a small amount of energetic frustration may enhance folding speed for certain proteins. In this study, we have investigated the conditions under which frustration increases the folding rate. We used a Cα structure-based model to simulate a group of proteins. We found that the free-energy barrier at the transition state (ΔF) correlates with nonnative-contact variation (ΔA), and the simulated proteins are clustered according to their fold motifs. These findings are corroborated by the Clementi-Plotkin analytical model. As a consequence, the optimum frustration regime for protein folding can be predicted analytically.

Effects of pH and Salt Concentration on Stability of a Protein G Variant Using Coarse-Grained Models

“…In the structure-based model (SBM), the residues of a protein are represented by individual beads centered in C a position (18,(48)(49)(50)(51). The energy of the protein is given by a Hamiltonian equation in which only the native interactions based on its native topology are taken into account (48).…”

“…Several levels of approximation have been proposed for protein models and for evaluating the electrostatic contributions of unfolding free energy (10)(11)(12)(13). In several of these studies, versions of structure-based models that include a fixed charge have been adopted to study the contribution of the electrostatic interaction in the unfolded state and the interaction between proteins and charged macromolecules (7,(14)(15)(16)(17)(18). Recently, to study pH effects on the folding dynamics of the N-terminal domain of ribosomal protein L9 (19), the constant-pH molecular dynamics (MD) method (CpHMD) (19)(20)(21) was implemented and the results showed a good level of agreement with the experiments.…”

Ensemble simulations: folding, unfolding and misfolding of a high-efficiency frameshifting RNA pseudoknot

“…Contacts between atomic pairs not observed in the simulated native state ensemble were classified as non-native contacts (NNC), an atomic-level analog of the recently-published NNC definition of Mouro et al. ( 29 ), and normalized using the largest quantity of non-native contacts observed. We emphasize that this latter normalization of non-native contacts may understate the overall degree of non-native character, and thus the degree of misfolding, present within a given structure.…”

Introdução ao problema de enovelamento de proteínas: uma abordagem utilizando modelos computacionais simplificados

“…Por outro lado, a superfície de energia das proteínas apresenta uma rugosidade intrínseca associada à frustração [49][50][51][52][53][54][55], que, como no caso de vidros de spin, é caraterizada por ∆E. Enquanto ∆E fica associado à propensão do sistema ficar armadilhado em mínimos locais, δE fornece um gradiente de energia na direção do mínimo global associado ao estado nativo como ilustrado na figura 3.…”

“…mais elaborados como a modificação dos potenciais utilizados, ou a adição de outros potenciais associados com a presença de frustração em proteínas, ou a adição de interação não-nativas eletrostáticas não discutidos em detalhes aqui. Existem um conjunto amplo de trabalhos na literatura abordando os efeitos da adição desses potencias na estabilidade e na dinâmica da proteína [45,54,55,82,96], inclusive, mais recentemente, com simulações de dinâmica molecular com pH constante [97][98][99][100]. Outra abordagem utilizando os modelos simplificados baseados em estrutura é o estudo de mudanças conformacionais envolvendo duas estruturas com o mínimo de energia.…”