Exploring the Folding Mechanism of Dimeric Superoxide Dismutase.

The Cu/Zn Human Superoxide Dismutase (SOD1) is a dimeric metalloenzyme whose genetic mutations are directly related to amyotrophic lateral sclerosis (ALS), so understanding its folding mechanism is of fundamental importance. Currently, the SOD1 dimer formation is studied via molecular dynamics simulations using a simplified structure-based model and an all-atom model. Results from the simplified model reveal a mechanism dependent on distances between monomers, which are limited by constraints to mimic concentration dependence.

Small Neutral Crowding Solute Effects on Protein Folding Thermodynamic Stability and Kinetics.

Molecular crowding is a ubiquitous phenomenon in biological systems, with significant consequences on protein folding and stability. Small compounds, such as the osmolyte trimethylamine -oxide (TMAO), can also present similar effects. To analyze the effects arising from these solute-like molecules, we performed a series of crowded coarse-grained folding simulations.

Computational study on the allosteric mechanism of IF4E-1 by 4E-interacting protein-1: Unravelling the determinants of mGTP cap recognition.

During their life cycle, parasites display a fine-tuned regulation of the mRNA translation through the differential expression of isoforms of eukaryotic translation initiation factor 4E (LeishIF4Es). The interaction between allosteric modulators such as 4E-interacting proteins (4E-IPs) and LeishIF4E affects the affinity of this initiation factor for the mRNA cap. Here, several computational approaches were employed to elucidate the molecular bases of the previously-reported allosteric modulation in exerted by 4E-IP1 (Lm4E-IP1) on eukaryotic translation initiation factor 4E 1 (LmIF4E-1).

Exploring Folding Aspects of Monomeric Superoxide Dismutase.

Recent studies have associated the absence of bound metals (Apo protein) and mutations in Cu-Zn Human Superoxide Dismutase (SOD1) with amyotrophic lateral sclerosis (ALS) disease, suggesting mechanisms of SOD1 aggregation. Using a structure-based model and modifying the energy of interaction between amino acids in the metal-binding site, we detected differences between the folding of the apo and holo proteins. The presence of metal ions decreases the free-energy barrier and also suggests that the folding pathway may change to reach the native state.

Diffusion of tRNA inside the ribosome is position-dependent.

In recent years, there has been a growing interest to quantify the energy landscape that governs ribosome dynamics. However, in order to quantitatively integrate theoretical predictions and experimental measurements, it is essential that one has a detailed understanding of the associated diffusive properties. Here, all-atom explicit-solvent simulations (50 μs of aggregate sampling) predict that the diffusion coefficient of a tRNA molecule will depend on its position within the ribosome.

Potential Implications for Designing Drugs Against the Brown Spider Venom Phospholipase-D.

Loxoscelism refers to the clinical symptoms that develop after brown spider bites. Brown spider venoms contain several phospholipase-D isoforms, which are the main toxins responsible for both the cutaneous and systemic effects of loxoscelism. Understanding of the phospholipase-D catalytic mechanism is crucial for the development of specific treatment that could reverse the toxic effects caused by the spider bite.

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

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.

Role of peptide-peptide interactions in aggregation: Protonectins observed in equilibrium and replica exchange molecular dynamics simulations.

Protonectin (ILGTILGLLKGL-NH2), a peptide extracted from the venom of the wasp Agelaia pallipes pallipes, promotes mast cell degranulation activity, antibiosis against Gram-positive and -negative bacteria, and chemotaxis in polymorphonucleated leukocytes. Another peptide from the same venom, Protonectin (1-6), corresponding to the first six residues of Protonectin, exhibits only chemotaxis. A 1:1 mixture of these two peptides showed positive synergistic antimicrobial effects, attributed to the formation of a heterodimer.

Capturing transition paths and transition states for conformational rearrangements in the ribosome.

To reveal the molecular determinants of biological function, one seeks to characterize the interactions that are formed in conformational and chemical transition states. In other words, what interactions govern the molecule's energy landscape? To accomplish this, it is necessary to determine which degrees of freedom can unambiguously identify each transition state. Here, we perform simulations of large-scale aminoacyl-transfer RNA (aa-tRNA) rearrangements during accommodation on the ribosome and project the dynamics along experimentally accessible atomic distances.

Analyzing the effect of homogeneous frustration in protein folding.

The energy landscape theory has been an invaluable theoretical framework in the understanding of biological processes such as protein folding, oligomerization, and functional transitions. According to the theory, the energy landscape of protein folding is funneled toward the native state, a conformational state that is consistent with the principle of minimal frustration. It has been accepted that real proteins are selected through natural evolution, satisfying the minimum frustration criterion.

The origin of nonmonotonic complex behavior and the effects of nonnative interactions on the diffusive properties of protein folding.

We present a method for calculating the configurational-dependent diffusion coefficient of a globular protein as a function of the global folding process. Using a coarse-grained structure-based model, we determined the diffusion coefficient, in reaction coordinate space, as a function of the fraction of native contacts formed Q for the cold shock protein (TmCSP). We find nonmonotonic behavior for the diffusion coefficient, with high values for the folded and unfolded ensembles and a lower range of values in the transition state ensemble.

Coordinate and time-dependent diffusion dynamics in protein folding.

We developed both analytical and simulation methods to explore the diffusion dynamics in protein folding. We found the diffusion as a quantitative measure of escape from local traps along the protein folding funnel with chosen reaction coordinates has two remarkable effects on kinetics. At a fixed coordinate, local escape time depends on the distribution of barriers around it, therefore the diffusion is often time distributed.

Configuration-dependent diffusion can shift the kinetic transition state and barrier height of protein folding.

We show that diffusion can play an important role in protein-folding kinetics. We explicitly calculate the diffusion coefficient of protein folding in a lattice model. We found that diffusion typically is configuration- or reaction coordinate-dependent.

Frustration and hydrophobicity interplay in protein folding and protein evolution.

A lattice model is used to study mutations and compacting effects on protein folding rates and folding temperature. In the context of protein evolution, we address the question regarding the best scenario for a polypeptide chain to fold: either a fast nonspecific collapse followed by a slow rearrangement to form the native structure or a specific collapse from the unfolded state with the simultaneous formation of the native state. This question is investigated for optimized sequences, whose native state has no frustrated contacts between monomers, and also for mutated sequences, whose native state has some degree of frustration.

Computational studies of the reversible domain swapping of p13suc1.

A minimalist representation of protein structures using a Go-like potential for interactions is implemented to investigate the mechanisms of the domain swapping of p13suc1, a protein that exists in two native conformations: a monomer and a domain-swapped dimer formed by the exchange of a beta-strand. Inspired by experimental studies which showed a similarity of the transition states for folding of the monomer and the dimer, in this study we justify this similarity in molecular descriptions. When intermediates are populated in the simulations, formation of a domain-swapped dimer initiates from the ensemble of unfolded monomers, given by the fact that the dimer formation occurs at the folding/unfolding temperature of the monomer (T(f)).

Specific and nonspecific collapse in protein folding funnels.

Experiments with fast folding proteins are beginning to address the relationship between collapse and folding. We investigate how different scenarios for folding can arise depending on whether the folding and collapse transitions are concurrent or whether a nonspecific collapse precedes folding. Many earlier studies have focused on the limit in which collapse is fast compared to the folding time; in this work we focus on the opposite limit where, at the folding temperature, collapse and folding occur simultaneously.