SPACER: server for predicting allosteric communication and effects of regulation

The SPACER server provides an interactive framework for exploring allosteric communication in proteins with different sizes, degrees of oligomerization and function. SPACER uses recently developed theoretical concepts based on the thermodynamic view of allostery. It proposes easily tractable and meaningful measures that allow users to analyze the effect of ligand binding on the intrinsic protein dynamics. The server shows potential allosteric sites and allows users to explore communication between the regulatory and functional sites. It is possible to explore, for instance, potential effector binding sites in a given structure as targets for allosteric drugs. As input, the server only requires a single structure. The server is freely available at http://allostery.bii.a-star.edu.sgpublishedVersio

Mutational signatures and mutable motifs in cancer genomes

Cancer is a genetic disorder, meaning that a plethora of different mutations, whether somatic or germ line, underlie the etiology of the ‘Emperor of Maladies’. Point mutations, chromosomal rearrangements and copy number changes, whether they have occurred spontaneously in predisposed individuals or have been induced by intrinsic or extrinsic (environmental) mutagens, lead to the activation of oncogenes and inactivation of tumor suppressor genes, thereby promoting malignancy. This scenario has now been recognized and experimentally confirmed in a wide range of different contexts. Over the past decade, a surge in available sequencing technologies has allowed the sequencing of whole genomes from liquid malignancies and solid tumors belonging to different types and stages of cancer, giving birth to the new field of cancer genomics. One of the most striking discoveries has been that cancer genomes are highly enriched with mutations of specific kinds. It has been suggested that these mutations can be classified into ‘families’ based on their mutational signatures. A mutational signature may be regarded as a type of base substitution (e.g. C:G to T:A) within a particular context of neighboring nucleotide sequence (the bases upstream and/or downstream of the mutation). These mutational signatures, supplemented by mutable motifs (a wider mutational context), promise to help us to understand the nature of the mutational processes that operate during tumor evolution because they represent the footprints of interactions between DNA, mutagens and the enzymes of the repair/replication/modification pathway

DNA polymerase η mutational signatures are found in a variety of different types of cancer

DNA polymerase (pol) η is a specialized error-prone polymerase with at least two quite different and contrasting cellular roles: to mitigate the genetic consequences of solar UV irradiation, and promote somatic hypermutation in the variable regions of immunoglobulin genes. Misregulation and mistargeting of pol η can compromise genome integrity. We explored whether the mutational signature of pol η could be found in datasets of human somatic mutations derived from normal and cancer cells. A substantial excess of single and tandem somatic mutations within known pol η mutable motifs was noted in skin cancer as well as in many other types of human cancer, suggesting that somatic mutations in A:T bases generated by DNA polymerase η are a common feature of tumorigenesis. Another peculiarity of pol ηmutational signatures, mutations in YCG motifs, led us to speculate that error-prone DNA synthesis opposite methylated CpG dinucleotides by misregulated pol η in tumors might constitute an additional mechanism of cytosine demethylation in this hypermutable dinucleotide

Prototypes of elementary functional loops unravel evolutionary connections between protein functions

Motivation: Earlier studies of protein structure revealed closed loops with a characteristic size 25–30 residues and ring-like shape as a basic universal structural element of globular proteins. Elementary functional loops (EFLs) have specific signatures and provide functional residues important for binding/activation and principal chemical transformation steps of the enzymatic reaction. The goal of this work is to show how these functional loops evolved from pre-domain peptides and to find a set of prototypes from which the EFLs of contemporary proteins originated

Molecular mechanisms of adaptation emerging from the physics and evolution of nucleic acids and proteins

DNA, RNA and proteins are major biological macromolecules that coevolve and adapt to environments as components of one highly interconnected system. We explore here sequence/structure determinants of mechanisms of adaptation of these molecules, links between them, and results of their mutual evolution. We complemented statistical analysis of genomic and proteomic sequences with folding simulations of RNA molecules, unraveling causal relations between compositional and sequence biases reflecting molecular adaptation on DNA, RNA and protein levels. We found many compositional peculiarities related to environmental adaptation and the life style. Specifically, thermal adaptation of protein-coding sequences in Archaea is characterized by a stronger codon bias than in Bacteria. Guanine and cytosine load in the third codon position is important for supporting the aerobic life style, and it is highly pronounced in Bacteria. The third codon position also provides a tradeoff between arginine and lysine, which are favorable for thermal adaptation and aerobicity, respectively. Dinucleotide composition provides stability of nucleic acids via strong base-stacking in ApG dinucleotides. In relation to coevolution of nucleic acids and proteins, thermostability-related demands on the amino acid composition affect the nucleotide content in the second codon position in Archaea

Exploring the evolution of protein function in Archaea

Abstract Background Despite recent progress in studies of the evolution of protein function, the questions what were the first functional protein domains and what were their basic building blocks remain unresolved. Previously, we introduced the concept of elementary functional loops (EFLs), which are the functional units of enzymes that provide elementary reactions in biochemical transformations. They are presumably descendants of primordial catalytic peptides. Results We analyzed distant evolutionary connections between protein functions in Archaea based on the EFLs comprising them. We show examples of the involvement of EFLs in new functional domains, as well as reutilization of EFLs and functional domains in building multidomain structures and protein complexes. Conclusions Our analysis of the archaeal superkingdom yields the dominating mechanisms in different periods of protein evolution, which resulted in several levels of the organization of biochemical function. First, functional domains emerged as combinations of prebiotic peptides with the very basic functions, such as nucleotide/phosphate and metal cofactor binding. Second, domain recombination brought to the evolutionary scene the multidomain proteins and complexes. Later, reutilization and de novo design of functional domains and elementary functional loops complemented evolution of protein function.</p

Highlights from the Eighth International Society for Computational Biology (ISCB) Student Council Symposium 2012

Abstract The report summarizes the scientific content of the annual symposium organized by the Student Council of the International Society for Computational Biology (ISCB) held in conjunction with the Intelligent Systems for Molecular Biology (ISMB) conference in Long Beach, California on July 13, 2012

Finding driver mutations in cancer: Elucidating the role of background mutational processes.

Identifying driver mutations in cancer is notoriously difficult. To date, recurrence of a mutation in patients remains one of the most reliable markers of mutation driver status. However, some mutations are more likely to occur than others due to differences in background mutation rates arising from various forms of infidelity of DNA replication and repair machinery, endogenous, and exogenous mutagens. We calculated nucleotide and codon mutability to study the contribution of background processes in shaping the observed mutational spectrum in cancer. We developed and tested probabilistic pan-cancer and cancer-specific models that adjust the number of mutation recurrences in patients by background mutability in order to find mutations which may be under selection in cancer. We showed that mutations with higher mutability values had higher observed recurrence frequency, especially in tumor suppressor genes. This trend was prominent for nonsense and silent mutations or mutations with neutral functional impact. In oncogenes, however, highly recurring mutations were characterized by relatively low mutability, resulting in an inversed U-shaped trend. Mutations not yet observed in any tumor had relatively low mutability values, indicating that background mutability might limit mutation occurrence. We compiled a dataset of missense mutations from 58 genes with experimentally validated functional and transforming impacts from various studies. We found that mutability of driver mutations was lower than that of passengers and consequently adjusting mutation recurrence frequency by mutability significantly improved ranking of mutations and driver mutation prediction. Even though no training on existing data was involved, our approach performed similarly or better to the state-of-the-art methods