Computer analysis of the relation between hydrogen bond stability in SOD1 mutants and the survival time of amyotrophic lateral sclerosis patients.

BACKGROUND AND OBJECTIVE: Mutations in the SOD1 protein can lead to the death of motor neurons, which, in turn, causes an incurable disease called amyotrophic lateral sclerosis (ALS). At the same time, the mechanism of the onset and development of this disease is not fully understood and is often contradictory. METHODS: Accelerated Molecular Dynamics as implemented in the OpenMM library, principal component analysis, regression analysis, random forest method. RESULTS: The stability of hydrogen bonds in 72 mutants of the SOD1 protein was calculated. Principal component analysis was carried out. Based on ten principal components acting as predictors, a multiple linear regression model was constructed. An analysis of the correlation of these ten principal components with the initial values of the stability of hydrogen bonds made it possible to characterize the contribution of known structurally and functionally important sites in the SOD1 to the scatter of ALS patients' survival time. CONCLUSION: Such an analysis made it possible to put forward hypotheses about the relationship between the stabilizing and destabilizing effects of mutations in different structurally and functionally important regions of SOD1 with the patients's survival time.

Learning the changes of barnase mutants thermostability from structural fluctuations obtained using anisotropic network modeling.

In biotechnology applications, rational design of new proteins with improved physico-chemical properties includes a number of important tasks. One of the greatest practical and fundamental challenges is the design of highly thermostable protein enzymes that maintain catalytic activity at high temperatures. This problem may be solved by introducing mutations into the wild-type enzyme protein. In this work, to predict the impact of such mutations in barnase protein we applied the anisotropic network modeling approach, revealing atomic fluctuations in structural regions that are changed in mutants compared to the wild-type protein. A regression model was constructed based on these structural features that can allow one to predict the thermal stability of new barnase mutants. Moreover, the analysis of regression model provides a mechanistic explanation of how the structural features can contribute to the thermal stability of barnase mutants.

Improved regression model to predict an impact of SOD1 mutations on ALS patients survival time based on analysis of hydrogen bond stability.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterised by the inevitable degeneration of central and peripheral motor neurons. Aggregation of mutant SOD1 is one of the molecular mechanisms underlying the onset of the disease. There are a number of regression models designed to predict the survival of patients based on an analysis of experimental data on thermostability, heterodimerisation energy, and changes in the hydrophobicity of SOD1 mutants. Previously, we proposed regression models linking the change in the stability of hydrogen bonds in mutant SOD1 calculated using molecular dynamics and elastic networks with patients survival time. In this study, these models were improved in terms of accuracy of survival time prediction by taking into account the variance of survival time values relative to the mean, the number of patients carrying each specific mutation, and the use of random forest regression as a regression method. The accuracy of the previous models was roughly 5.2 years while the accuracy of the new ones are up to 4 years. The model is also superior to those published by other authors. It was found that the hydrogen bonds important for prediction of survival time are formed by residues at positions located in the regions of the protein responsible for aggregation as well as in structural and functionally important sites.

Correction to: selected articles from Belyaev Conference 2017: structural biology.

After publication of the article [1], it has been brought to our attention that there is a discrepancy between the publication date on the pdf and online formats. The date on the pdf is 6th February 2018 and online is 5th February 2018. The correct publication date is the one on the pdf, 6th February 2018.

Molecular mechanisms underlying the impact of mutations in SOD1 on its conformational properties associated with amyotrophic lateral sclerosis as revealed with molecular modelling.

BACKGROUND: So far, little is known about the molecular mechanisms of amyotrophic lateral sclerosis onset and progression caused by SOD1 mutations. One of the hypotheses is based on SOD1 misfolding resulting from mutations and subsequent deposition of its cytotoxic aggregates. This hypothesis is complicated by the fact that known SOD1 mutations of similar clinical effect could be distributed over the whole protein structure. RESULTS: In this work, a measure of hydrogen bond stability in conformational states was studied with elastic network analysis of 35 SOD1 mutants. Twenty-eight hydrogen bonds were detected in nine of 35 mutants with their stability being significantly different from that with the wild-type. These hydrogen bonds were formed by the amino acid residues known from the literature to be located in contact between SOD1 aggregates. Additionally, residues disposed between copper binding sites of both protein subunits were found from the models to form a stiff core, which can be involved in mechanical impulse transduction between these active centres. CONCLUSIONS: The modelling highlights that both stability of the copper binding site and stability of the dimer can play an important role in ALS progression.

Regression model for predicting pathogenic properties of SOD1 mutants based on the analysis of conformational stability and conservation of hydrogen bonds.

Intracellular aggregation of proteins is thought to be involved in the aetiology of various neurodegenerative diseases. In particular, mutations in the SOD1 gene are linked to the familial form of amyotrophic lateral sclerosis (ALS). Recently, we developed a regression model for estimating the survival time of ALS patients carrying mutations in SOD1. This model was built based on an analysis of the stability of hydrogen bonds formed in SOD1 mutant proteins during a molecular dynamics (MD) simulation. In the present paper, the regression model was improved by taking into account a new hydrogen-bond property that reflects the conservation measure of a hydrogen bond in the space of protein conformational states. Conformational conservation of hydrogen bonds, being obtained with elastic network (EN) models, allowed us to find eight hydrogen bonds that might affect the pathogenic SOD1 mutants' properties in addition to the bonds that were found via MD in our previous work. The correlation coefficient between survival time of patients with ALS-linked mutations in SOD1 predicted within the improved model and that observed in the literature was 0.91. SOD1 amino acid residues forming these pathogenic hydrogen bonds are found in zinc-binding and electrostatic loops as well as at zinc-binding sites and are in contact with SOD1 aggregates, which implies that these regions are sensitive to perturbations from pathogenic mutations.

Dynamic properties of SOD1 mutants can predict survival time of patients carrying familial amyotrophic lateral sclerosis.

One of the reasons for the death of motor neurons of the brain and spinal cord in patients with amyotrophic lateral sclerosis is known to be formation of subcellular protein aggregates that are caused by mutations in the SOD1 gene. Patient survival time was earlier shown to have limiting correlation with thermostability change of SOD1 mutant forms of patients' carriers. We hypothesized that aggregation of mutant SOD1 may occur not only due to the protein destabilization, but through formation of novel interatomic bonds which stabilize "pathogenic" conformations of the mutant as well. To estimate these effects in the present paper, we performed statistical analysis of occupancy of intramolecular hydrogen bonds, hydrogen bonds between the protein and water molecules, and water bridges with use of molecular dynamics simulation for 38 mutant SOD1 forms. Multiple regression model based on these kinds of bonds demonstrated correlation with patient survival time significantly better (R = .9, p-value < 10-11) than the thermostability of SOD1 mutants only. It was shown that the occupancy of intramolecular hydrogen bonds between amino acid residues is a key determinant (R = .89, p-value < 10-10) in predicting patients' survival time.

Molecular dynamics simulations of the Nip7 proteins from the marine deep- and shallow-water Pyrococcus species.

BACKGROUND: The identification of the mechanisms of adaptation of protein structures to extreme environmental conditions is a challenging task of structural biology. We performed molecular dynamics (MD) simulations of the Nip7 protein involved in RNA processing from the shallow-water (P. furiosus) and the deep-water (P. abyssi) marine hyperthermophylic archaea at different temperatures (300 and 373 K) and pressures (0.1, 50 and 100 MPa). The aim was to disclose similarities and differences between the deep- and shallow-sea protein models at different temperatures and pressures. RESULTS: The current results demonstrate that the 3D models of the two proteins at all the examined values of pressures and temperatures are compact, stable and similar to the known crystal structure of the P. abyssi Nip7. The structural deviations and fluctuations in the polypeptide chain during the MD simulations were the most pronounced in the loop regions, their magnitude being larger for the C-terminal domain in both proteins. A number of highly mobile segments the protein globule presumably involved in protein-protein interactions were identified. Regions of the polypeptide chain with significant difference in conformational dynamics between the deep- and shallow-water proteins were identified. CONCLUSIONS: The results of our analysis demonstrated that in the examined ranges of temperatures and pressures, increase in temperature has a stronger effect on change in the dynamic properties of the protein globule than the increase in pressure. The conformational changes of both the deep- and shallow-sea protein models under increasing temperature and pressure are non-uniform. Our current results indicate that amino acid substitutions between shallow- and deep-water proteins only slightly affect overall stability of two proteins. Rather, they may affect the interactions of the Nip7 protein with its protein or RNA partners.