Motivation: Mutations play fundamental roles in evolution by introducing diversity into genomes. Missense mutations in structural genes may become either selectively advantageous or disadvantageous to the organism by affecting protein stability and/or interfering with interactions between partners. Thus, the ability to predict the impact of mutations on protein stability and interactions is of significant value, particularly in understanding the effects of Mendelian and somatic mutations on the progression of disease. Here, we propose a novel approach to the study of missense mutations, called mCSM, which relies on graph-based signatures. These encode distance patterns between atoms and are used to represent the protein residue environment and to train predictive models. To understand the roles of mutations in disease, we have evaluated their impacts not only on protein stability but also on protein–protein and protein–nucleic acid interactions. Results: We show that mCSM performs as well as or better than other methods that are used widely. The mCSM signatures were successfully used in different tasks demonstrating that the impact of a mutation can be correlated with the atomic-distance patterns surrounding an amino acid residue. We showed that mCSM can predict stability changes of a wide range of mutations occurring in the tumour suppressor protein p53, demonstrating the applicability of the proposed method in a challenging disease scenario. Availability and implementation: A web server is available at http:// structure.bioc.cam.ac.uk/mcsm.

https://minerva-access.unimelb.edu.au/bitstream/handle/11343/216427/mCSM: predicting the effects of mutations in proteins using graph-based signatures.pdf

mCSM: predicting the effects of mutations in proteins using graph-based signatures

The traditional computational modeling of protein structure, dynamics, and interactions remains difficult for many protein systems. It is mostly due to the size of protein conformational spaces and required simulation time scales that are still too large to be studied in atomistic detail. Lowering the level of protein representation from all-atom to coarse-grained opens up new possibilities for studying protein systems. In this review we provide an overview of coarse-grained models focusing on their design, including choices of representation, models of energy functions, sampling of conformational space, and applications in the modeling of protein structure, dynamics, and interactions. A more detailed description is given for applications of coarse-grained models suitable for efficient combinations with all-atom simulations in multiscale modeling strategies.

/pdf/coarse-grained-protein-models-and-their-applications-1o2zj49ltx.pdf

Coarse-Grained Protein Models and Their Applications

Proteins are highly dynamic molecules, whose function is intrinsically linked to their molecular motions. Despite the pivotal role of protein dynamics, their computational simulation cost has led to most structure-based approaches for assessing the impact of mutations on protein structure and function relying upon static structures. Here we present DynaMut, a web server implementing two distinct, well established normal mode approaches, which can be used to analyze and visualize protein dynamics by sampling conformations and assess the impact of mutations on protein dynamics and stability resulting from vibrational entropy changes. DynaMut integrates our graph-based signatures along with normal mode dynamics to generate a consensus prediction of the impact of a mutation on protein stability. We demonstrate our approach outperforms alternative approaches to predict the effects of mutations on protein stability and flexibility (P-value < 0.001), achieving a correlation of up to 0.70 on blind tests. DynaMut also provides a comprehensive suite for protein motion and flexibility analysis and visualization via a freely available, user friendly web server at http://biosig.unimelb.edu.au/dynamut/.

https://minerva-access.unimelb.edu.au/bitstream/handle/11343/216409/DynaMut: predicting the impact of mutations on protein conformation, flexibility and stability.pdf

DynaMut: predicting the impact of mutations on protein conformation, flexibility and stability

Cancer genome and other sequencing initiatives are generating extensive data on non-synonymous single nucleotide polymorphisms (nsSNPs) in human and other genomes. In order to understand the impacts of nsSNPs on the structure and function of the proteome, as well as to guide protein engineering, accurate in silicomethodologies are required to study and predict their effects on protein stability. Despite the diversity of available computational methods in the literature, none has proven accurate and dependable on its own under all scenarios where mutation analysis is required. Here we present DUET, a web server for an integrated computational approach to study missense mutations in proteins. DUET consolidates two complementary approaches (mCSM and SDM) in a consensus prediction, obtained by combining the results of the separate methods in an optimized predictor using Support Vector Machines (SVM). We demonstrate that the proposed method improves overall accuracy of the predictions in comparison with either method individually and performs as well as or better than similar methods. The DUET web server is freely and openly available at http://structure.bioc.cam.ac.uk/duet.

https://minerva-access.unimelb.edu.au/bitstream/handle/11343/216424/DUET: a server for predicting effects of mutations on protein stability using an integrated computational approach.pdf

DUET: A Server for Predicting Effects of Mutations on Protein Stability Using an Integrated Computational Approach

Protein engineering through machine-learning-guided directed evolution enables the optimization of protein functions. Machine-learning approaches predict how sequence maps to function in a data-driven manner without requiring a detailed model of the underlying physics or biological pathways. Such methods accelerate directed evolution by learning from the properties of characterized variants and using that information to select sequences that are likely to exhibit improved properties. Here we introduce the steps required to build machine-learning sequence-function models and to use those models to guide engineering, making recommendations at each stage. This review covers basic concepts relevant to the use of machine learning for protein engineering, as well as the current literature and applications of this engineering paradigm. We illustrate the process with two case studies. Finally, we look to future opportunities for machine learning to enable the discovery of unknown protein functions and uncover the relationship between protein sequence and function.

/pdf/machine-learning-guided-directed-evolution-for-protein-2kyvo4u8ck.pdf

Machine-learning-guided directed evolution for protein engineering.

Motivation: The rational design of proteins with modified properties, through amino acid substitutions, is of crucial importance in a large variety of applications. Given the huge number of possible substitutions, every protein engineering project would benefit strongly from the guidance of in silico methods able to predict rapidly, and with reasonable accuracy, the stability changes resulting from all possible mutations in a protein.

Results: We exploit newly developed statistical potentials, based on a formalism that highlights the coupling between four protein sequence and structure descriptors, and take into account the amino acid volume variation upon mutation. The stability change is expressed as a linear combination of these energy functions, whose proportionality coefficients vary with the solvent accessibility of the mutated residue and are identified with the help of a neural network. A correlation coefficient of R = 0.63 and a root mean square error of σc = 1.15 kcal/mol between measured and predicted stability changes are obtained upon cross-validation. These scores reach R = 0.79, and σc = 0.86 kcal/mol after exclusion of 10% outliers. The predictive power of our method is shown to be significantly higher than that of other programs described in the literature.

Availability: http://babylone.ulb.ac.be/popmusic 

Contact: ydehouck@ulb.ac.be

Supplementary information:Supplementary data are available at Bioinformatics online.

Fast and accurate predictions of protein stability changes upon mutations using statistical potentials and neural networks

Macroscopic modelling of overflow metabolism and model based optimization of hybridoma cell fed-batch cultures

State estimation is a significant problem in biotechnological processes, due to the general lack of hardware sensor measurements of the variables describing the process dynamics The objective of this paper is to review a number of software sensor design methods, including extended Kalman filters, receding-horizon observers, asymptotic observers, and hybrid observers, which can be efficiently applied to bioprocesses These several methods are illustrated with simulation and real-life case studies

Software sensors for bioprocesses

In this study, a class of dynamic models based on metabolic reaction pathways is analyzed, showing that systems with complex intracellular reaction networks can be represented by macroscopic reactions relating extracellular components only. Based on rigorous assumptions, the model reduction procedure is systematic and allows an equivalent 'input-output' representation of the system to be derived. The procedure is illustrated with a few examples.

Dynamic modeling of complex biological systems: a link between metabolic and macroscopic description.

The exponential observers (extended Kalman or Luenberger observers, high gain observers) allow the use of a tuning parameter for managing the rate of convergence of the state estimate towards the true state. But their results are strongly dependent on the model quality (especially the kinetic model in bioprocesses). On the other hand, asymptotic observers (like the observer of Bastin and Dochain) have a rate of convergence which is a function of the experimental conditions (namely the dilution rate). However, this lack of tuning parameter is compensated by the absence of need for any kinetic model. In this paper, a hybrid technique is proposed which allows to jointly estimate the state and identify on-line the confidence on the kinetic model. The two limit cases (100 and 0 confidence) allow to recover rigorously the extended Kalman filter and the asymptotic observer of Bastin and Dochain. A simulation example (a fed-batch bacterial culture) is proposed and exhibits very satisfactory results.

Philippe Bogaerts

Papers

Fast and accurate predictions of protein stability changes upon mutations using statistical potentials and neural networks

Macroscopic modelling of overflow metabolism and model based optimization of hybridoma cell fed-batch cultures

Software sensors for bioprocesses

Dynamic modeling of complex biological systems: a link between metabolic and macroscopic description.

A hybrid asymptotic-Kalman observer for bioprocesses