A structural systems biology approach for quantifying the systemic consequences of missense mutations in proteins

Gauging the systemic effects of non-synonymous single nucleotide polymorphisms (nsSNPs) is an important topic in the pursuit of personalized medicine. However, it is a non-trivial task to understand how a change at the protein structure level eventually affects a cell's behavior. This is because complex information at both the protein and pathway level has to be integrated. Given that the idea of integrating both protein and pathway dynamics to estimate the systemic impact of missense mutations in proteins remains predominantly unexplored, we investigate the practicality of such an approach by formulating mathematical models and comparing them with experimental data to study missense mutations. We present two case studies: (1) interpreting systemic perturbation for mutations within the cell cycle control mechanisms (G2 to mitosis transition) for yeast; (2) phenotypic classification of neuron-related human diseases associated with mutations within the mitogen-activated protein kinase (MAPK) pathway. We show that the application of simplified mathematical models is feasible for understanding the effects of small sequence changes on cellular behavior. Furthermore, we show that the systemic impact of missense mutations can be effectively quantified as a combination of protein stability change and pathway perturbation

PROTDES: CHARMM toolbox for computational protein design

We present an open-source software able to automatically mutate any residue positions and find the best aminoacids in an arbitrary protein structure without requiring pairwise approximations. Our software, PROTDES, is based on CHARMM and it searches automatically for mutations optimizing a protein folding free energy. PROTDES allows the integration of molecular dynamics within the protein design. We have implemented an heuristic optimization algorithm that iteratively searches the best aminoacids and their conformations for an arbitrary set of positions within a structure. Our software allows CHARMM users to perform protein design calculations and to create their own procedures for protein design using their own energy functions. We show this by implementing three different energy functions based on different solvent treatments: surface area accessibility, generalized Born using molecular volume and an effective energy function. PROTDES, a tutorial, parameter sets, configuration tools and examples are freely available at http://soft.synth-bio.org/protdes.html

Modeling of protein complexes and molecular assemblies with pyDock

The study of the 3D structural details of protein interactions is essential to understand biomolecular functions at the molecular level. In this context, the limited availability of experimental structures of protein–protein complexes at atomic resolution is propelling the development of computational docking methods that aim to complement the current structural coverage of protein interactions. One of these docking approaches is pyDock, which uses van der Waals, electrostatics, and desolvation energy to score docking poses generated by a variety of sampling methods, typically FTDock or ZDOCK. The method has shown a consistently good prediction performance in community-wide assessment experiments like CAPRI or CASP, and has provided biological insights and insightful interpretation of experiments by modeling many biomolecular interactions of biomedical and biotechnological interest. Here, we describe in detail how to perform structural modeling of protein assemblies with pyDock, and the application of its modules to different biomolecular recognition phenomena, such as modeling of binding mode, interface, and hot-spot prediction, use of restraints based on experimental data, inclusion of low-resolution structural data, binding affinity estimation, or modeling of homo- and hetero-oligomeric assemblies.This work was supported by the Spanish Ministry of Science (grant BIO2016-79930-R).Peer ReviewedPostprint (author's final draft

What Is Known About Vertex Cover Kernelization?

25 pages, 10 figures. Appeared in volume 11011 of LNCS, pages 330-356, see Reference [29] in the text. Compared to [29], this arXiv-upload contains a fixed version of Reduction R.8, the order of presentation of Reductions R.6 and R.7 has been switched, and a few observations have been added in Section 3International audienceWe are pleased to dedicate this survey on kernelization of the Vertex Cover problem, to Professor Juraj Hromkovi\v{c} on the occasion of his 60th birthday. The Vertex Cover problem is often referred to as the Drosophila of parameterized complexity. It enjoys a long history. New and worthy perspectives will always be demonstrated first with concrete results here. This survey discusses several research directions in Vertex Cover kernelization. The Barrier Degree of Vertex Cover kernelization is discussed. We have reduction rules that kernelize vertices of small degree, including in this paper new results that reduce graphs almost to minimum degree five. Can this process go on forever? What is the minimum vertex-degree barrier for polynomial-time kernelization? Assuming the Exponential-Time Hypothesis, there is a minimum degree barrier. The idea of automated kernelization is discussed. We here report the first experimental results of an AI-guided branching algorithm for Vertex Cover whose logic seems amenable for application in finding reduction rules to kernelize small-degree vertices. The survey highlights a central open problem in parameterized complexity. Happy Birthday, Juraj