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Ultra-large make-on-demand compound libraries now contain billions of readily available compounds. This represents a golden opportunity for in-silico drug discovery. One challenge, however, is the time and computational cost of an…
Biological systems have evolved to amazingly complex states, yet we do not understand in general how evolution operates to generate increasing genetic and functional complexity. Molecular recognition sites are short genome segments or…
The rate of mRNA translation depends on the initiation, elongation, and termination rates of ribosomes along the mRNA. These rates depend on many "local" factors like the abundance of free ribosomes and tRNA molecules in the vicinity of the…
With the increasing release of powerful language models trained on large code corpus (e.g. CodeBERT was trained on 6.4 million programs), a new family of mutation testing tools has arisen with the promise to generate more "natural" mutants…
Drug resistance is a major threat to the global health and a significant concern throughout the clinical treatment of diseases and drug development. The mutation in proteins that is related to drug binding is a common cause for adaptive…
One of the causes of high fidelity of copying in biological systems is kinetic discrimination. In this mechanism larger dissipation and copying velocity result in improved copying accuracy. We consider a model of a polymerase which…
Many native structures of proteins accomodate complex topological motifs such as knots, lassos, and other geometrical entanglements. How proteins can fold quickly even in the presence of such topological obstacles is a debated question in…
Mutation testing is a standard technique to evaluate the quality of a test suite. Due to its computationally intensive nature, many approaches have been proposed to make this technique feasible in real case scenarios. Among these…
Proteins are traditionally optimized through the costly construction and measurement of many mutants. Active Learning-assisted Directed Evolution (ALDE) alleviates that cost by predicting the best improvements and iteratively testing…
Empirical substitution matrices represent the average tendencies of substitutions over various protein families by sacrificing gene-level resolution. We develop a codon-based model, in which mutational tendencies of codon, a genetic code,…
Protein mutations can significantly influence protein solubility, which results in altered protein functions and leads to various diseases. Despite of tremendous effort, machine learning prediction of protein solubility changes upon…
Accurate estimation of evolutionary distances between taxa is important for many phylogenetic reconstruction methods. In the case of bacteria, distances can be estimated using a range of different evolutionary models, from single nucleotide…
A protein's function depends critically on its conformational ensemble, a collection of energy weighted structures whose balance depends on temperature and environment. Though recent deep learning (DL) methods have substantially advanced…
We experimentally demonstrate that information replication by templated ligation of DNA strands inherits a kinetic proofreading mechanism and achieves significant error suppression through cascade replication. A simple simulation model…
Potts statistical models have become a popular and promising way to analyze mutational covariation in protein Multiple Sequence Alignments (MSAs) in order to understand protein structure, function and fitness. But the statistical…
Protein Language Models (PLMs) have emerged as performant and scalable tools for predicting the functional impact and clinical significance of protein-coding variants, but they still lag experimental accuracy. Here, we present a novel…
Despite being self-supervised, protein language models have shown remarkable performance in fundamental biological tasks such as predicting impact of genetic variation on protein structure and function. The effectiveness of these models on…
Mutations create the genetic diversity on which selective pressures can act, yet also create structural instability in proteins. How, then, is it possible for organisms to ameliorate mutation-induced perturbations of protein stability while…
The majority of mammalian genomic transcripts do not directly code for proteins and it is currently believed that most of these are not under evolutionary constraint. However given the abundance non-coding RNA (ncRNA) and its strong…
Phylogenetics uses alignments of molecular sequence data to learn about evolutionary trees relating species. Along branches, sequence evolution is modelled using a continuous-time Markov process characterised by an instantaneous rate…