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Article ; Online: Back in time to the Gly-rich prototype of the phosphate binding elementary function.

Zheng, Zejun / Goncearenco, Alexander / Berezovsky, Igor N

Current research in structural biology

2024 Volume 7, Page(s) 100142

Abstract: Binding of nucleotides and their derivatives is one of the most ancient elementary functions dating back to the Origin of Life. We review here the works considering one of the key elements in binding of (di)nucleotide-containing ligands - phosphate ... ...

Abstract	Binding of nucleotides and their derivatives is one of the most ancient elementary functions dating back to the Origin of Life. We review here the works considering one of the key elements in binding of (di)nucleotide-containing ligands - phosphate binding. We start from a brief discussion of major participants, conditions, and events in prebiotic evolution that resulted in the Origin of Life. Tracing back to the basic functions, including metal and phosphate binding, and, potentially, formation of primitive protein-protein interactions, we focus here on the phosphate binding. Critically assessing works on the structural, functional, and evolutionary aspects of phosphate binding, we perform a simple computational experiment reconstructing its most ancient and generic sequence prototype. The profiles of the phosphate binding signatures have been derived in form of position-specific scoring matrices (PSSMs), their peculiarities depending on the type of the ligands have been analyzed, and evolutionary connections between them have been delineated. Then, the apparent prototype that gave rise to all relevant phosphate-binding signatures had also been reconstructed. We show that two major signatures of the phosphate binding that discriminate between the binding of dinucleotide- and nucleotide-containing ligands are GxGxxG and GxxGxG, respectively. It appears that the signature archetypal for dinucleotide-containing ligands is more generic, and it can frequently bind phosphate groups in nucleotide-containing ligands as well. The reconstructed prototype's key signature GxGGxG underlies the role of glycine residues in providing flexibility and interactions necessary for binding the phosphate groups. The prototype also contains other ancient amino acids, valine, and alanine, showing versatility towards evolutionary design and functional diversification.
Language	English
Publishing date	2024-04-09
Publishing country	Netherlands
Document type	Journal Article ; Review
ISSN	2665-928X
ISSN (online)	2665-928X
DOI	10.1016/j.crstbi.2024.100142
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Article ; Online: Deriving and Using Descriptors of Elementary Functions in Rational Protein Design.

Yin, Melvin / Goncearenco, Alexander / Berezovsky, Igor N

Frontiers in bioinformatics

2021 Volume 1, Page(s) 657529

Abstract: The rational design of proteins with desired functions requires a comprehensive description of the functional building blocks. The evolutionary conserved functional units constitute nature's toolbox; however, they are not readily available to protein ... ...

Abstract	The rational design of proteins with desired functions requires a comprehensive description of the functional building blocks. The evolutionary conserved functional units constitute nature's toolbox; however, they are not readily available to protein designers. This study focuses on protein units of subdomain size that possess structural properties and amino acid residues sufficient to carry out elementary reactions in the catalytic mechanisms. The interactions within such elementary functional loops (ELFs) and the interactions with the surrounding protein scaffolds constitute the descriptor of elementary function. The computational approach to deriving descriptors directly from protein sequences and structures and applying them in rational design was implemented in a proof-of-concept DEFINED-PROTEINS software package. Once the descriptor is obtained, the ELF can be fitted into existing or novel scaffolds to obtain the desired function. For instance, the descriptor may be used to determine the necessary spatial restraints in a fragment-based grafting protocol. We illustrated the approach by applying it to well-known cases of ELFs, including phosphate-binding P-loop, diphosphate-binding glycine-rich motif, and calcium-binding EF-hand motif, which could be used to jumpstart templates for user applications. The DEFINED-PROTEINS package is available for free at https://github.com/MelvinYin/Defined_Proteins.
Language	English
Publishing date	2021-04-13
Publishing country	Switzerland
Document type	Journal Article
ISSN	2673-7647
ISSN (online)	2673-7647
DOI	10.3389/fbinf.2021.657529
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Article: From sequence to function through structure: Deep learning for protein design.

Ferruz, Noelia / Heinzinger, Michael / Akdel, Mehmet / Goncearenco, Alexander / Naef, Luca / Dallago, Christian

Computational and structural biotechnology journal

2022 Volume 21, Page(s) 238–250

Abstract: The process of designing biomolecules, in particular proteins, is witnessing a rapid change in available tooling and approaches, moving from design through physicochemical force fields, to producing plausible, complex sequences fast via end-to-end ... ...

Abstract	The process of designing biomolecules, in particular proteins, is witnessing a rapid change in available tooling and approaches, moving from design through physicochemical force fields, to producing plausible, complex sequences fast via end-to-end differentiable statistical models. To achieve conditional and controllable protein design, researchers at the interface of artificial intelligence and biology leverage advances in natural language processing (NLP) and computer vision techniques, coupled with advances in computing hardware to learn patterns from growing biological databases, curated annotations thereof, or both. Once learned, these patterns can be used to provide novel insights into mechanistic biology and the design of biomolecules. However, navigating and understanding the practical applications for the many recent protein design tools is complex. To facilitate this, we 1) document recent advances in deep learning (DL) assisted protein design from the last three years, 2) present a practical pipeline that allows to go from
Language	English
Publishing date	2022-11-19
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2022.11.014
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Article ; Online: Protein function from its emergence to diversity in contemporary proteins.

Goncearenco, Alexander / Berezovsky, Igor N

Physical biology

2015 Volume 12, Issue 4, Page(s) 45002

Abstract: The goal of this work is to learn from nature the rules that govern evolution and the design of protein function. The fundamental laws of physics lie in the foundation of the protein structure and all stages of the protein evolution, determining optimal ... ...

Abstract	The goal of this work is to learn from nature the rules that govern evolution and the design of protein function. The fundamental laws of physics lie in the foundation of the protein structure and all stages of the protein evolution, determining optimal sizes and shapes at different levels of structural hierarchy. We looked back into the very onset of the protein evolution with a goal to find elementary functions (EFs) that came from the prebiotic world and served as building blocks of the first enzymes. We defined the basic structural and functional units of biochemical reactions-elementary functional loops. The diversity of contemporary enzymes can be described via combinations of a limited number of elementary chemical reactions, many of which are performed by the descendants of primitive prebiotic peptides/proteins. By analyzing protein sequences we were able to identify EFs shared by seemingly unrelated protein superfamilies and folds and to unravel evolutionary relations between them. Binding and metabolic processing of the metal- and nucleotide-containing cofactors and ligands are among the most abundant ancient EFs that became indispensable in many natural enzymes. Highly designable folds provide structural scaffolds for many different biochemical reactions. We show that contemporary proteins are built from a limited number of EFs, making their analysis instrumental for establishing the rules for protein design. Evolutionary studies help us to accumulate the library of essential EFs and to establish intricate relations between different folds and functional superfamilies. Generalized sequence-structure descriptors of the EF will become useful in future design and engineering of desired enzymatic functions.
MeSH term(s)	Archaea/chemistry ; Archaea/enzymology ; Archaea/genetics ; Archaea/metabolism ; Archaeal Proteins/chemistry ; Archaeal Proteins/genetics ; Archaeal Proteins/metabolism ; Evolution, Molecular ; Models, Genetic ; Protein Conformation
Chemical Substances	Archaeal Proteins
Language	English
Publishing date	2015-06-09
Publishing country	England
Document type	Journal Article
ZDB-ID	2133216-2
ISSN	1478-3975 ; 1478-3967
ISSN (online)	1478-3975
ISSN	1478-3967
DOI	10.1088/1478-3975/12/4/045002
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Article ; Online: Finding driver mutations in cancer: Elucidating the role of background mutational processes.

Brown, Anna-Leigh / Li, Minghui / Goncearenco, Alexander / Panchenko, Anna R

PLoS computational biology

2019 Volume 15, Issue 4, Page(s) e1006981

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Codon/genetics ; Computational Biology ; DNA Replication/genetics ; Humans ; Mutation/genetics ; Mutation/physiology ; Neoplasms/genetics ; Oncogenes/genetics
Chemical Substances	Codon
Language	English
Publishing date	2019-04-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1006981
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Article ; Online: Data sets on human histone interaction networks.

Peng, Yunhui / Markov, Yaroslav / Goncearenco, Alexander / Landsman, David / Panchenko, Anna R

Data in brief

2020 Volume 33, Page(s) 106555

Abstract: Here, we present the data of human histone interactomes generated and analysed in the research article by Peng et al., 2020 [1]. The histone interactome data provide a comprehensive mapping of human histone/nucleosome interaction networks by using ... ...

Abstract	Here, we present the data of human histone interactomes generated and analysed in the research article by Peng et al., 2020 [1]. The histone interactome data provide a comprehensive mapping of human histone/nucleosome interaction networks by using different data sources from the structural, chemical cross-linking, and high-throughput studies. The histone interactions are presented at different levels of granularity in networks, including protein, domain, and residue-levels. All human histone interactome Cytoscape session files are available at https://github.com/Panchenko-Lab/Human-histone-interactome.
Language	English
Publishing date	2020-11-21
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2786545-9
ISSN	2352-3409 ; 2352-3409
ISSN (online)	2352-3409
ISSN	2352-3409
DOI	10.1016/j.dib.2020.106555
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Article ; Online: Human Histone Interaction Networks: An Old Concept, New Trends.

Peng, Yunhui / Markov, Yaroslav / Goncearenco, Alexander / Landsman, David / Panchenko, Anna R

Journal of molecular biology

2020 Volume 433, Issue 6, Page(s) 166684

Abstract: To elucidate the properties of human histone interactions on the large scale, we perform a comprehensive mapping of human histone interaction networks by using data from structural, chemical cross-linking and various high-throughput studies. Histone ... ...

Abstract	To elucidate the properties of human histone interactions on the large scale, we perform a comprehensive mapping of human histone interaction networks by using data from structural, chemical cross-linking and various high-throughput studies. Histone interactomes derived from different data sources show limited overlap and complement each other. It inspires us to integrate these data into the combined histone global interaction network which includes 5308 proteins and 10,330 interactions. The analysis of topological properties of the human histone interactome reveals its scale free behavior and high modularity. Our study of histone binding interfaces uncovers a remarkably high number of residues involved in interactions between histones and non-histone proteins, 80-90% of residues in histones H3 and H4 have at least one binding partner. Two types of histone binding modes are detected: interfaces conserved in most histone variants and variant specific interfaces. Finally, different types of chromatin factors recognize histones in nucleosomes via distinct binding modes, and many of these interfaces utilize acidic patches among other sites. Interaction networks are available at https://github.com/Panchenko-Lab/Human-histone-interactome.
MeSH term(s)	Binding Sites ; Chromosomal Proteins, Non-Histone/chemistry ; Chromosomal Proteins, Non-Histone/genetics ; Chromosomal Proteins, Non-Histone/metabolism ; DNA/chemistry ; DNA/genetics ; DNA/metabolism ; Databases, Protein ; Histones/chemistry ; Histones/genetics ; Histones/metabolism ; Humans ; Internet ; Nucleic Acid Conformation ; Nucleosomes/chemistry ; Nucleosomes/metabolism ; Nucleosomes/ultrastructure ; Protein Binding ; Protein Conformation, alpha-Helical ; Protein Conformation, beta-Strand ; Protein Interaction Domains and Motifs ; Protein Interaction Maps ; Software
Chemical Substances	Chromosomal Proteins, Non-Histone ; Histones ; Nucleosomes ; DNA (9007-49-2)
Language	English
Publishing date	2020-10-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2020.10.018
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Article ; Online: Annotating Mutational Effects on Proteins and Protein Interactions: Designing Novel and Revisiting Existing Protocols.

Li, Minghui / Goncearenco, Alexander / Panchenko, Anna R

Methods in molecular biology (Clifton, N.J.)

2017 Volume 1550, Page(s) 235–260

Abstract: In this review we describe a protocol to annotate the effects of missense mutations on proteins, their functions, stability, and binding. For this purpose we present a collection of the most comprehensive databases which store different types of ... ...

Abstract	In this review we describe a protocol to annotate the effects of missense mutations on proteins, their functions, stability, and binding. For this purpose we present a collection of the most comprehensive databases which store different types of sequencing data on missense mutations, we discuss their relationships, possible intersections, and unique features. Next, we suggest an annotation workflow using the state-of-the art methods and highlight their usability, advantages, and limitations for different cases. Finally, we address a particularly difficult problem of deciphering the molecular mechanisms of mutations on proteins and protein complexes to understand the origins and mechanisms of diseases.
MeSH term(s)	Binding Sites ; Computational Biology/methods ; Databases, Genetic ; Hydrogen Bonding ; Models, Molecular ; Molecular Sequence Annotation ; Mutation ; Protein Binding ; Protein Conformation ; Protein Interaction Domains and Motifs ; Protein Interaction Mapping/methods ; Protein Interaction Maps ; Protein Stability ; Proteins/chemistry ; Proteins/genetics ; Proteins/metabolism ; Software ; Web Browser ; Workflow
Chemical Substances	Proteins
Language	English
Publishing date	2017-02-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-6747-6_17
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Article ; Online: The fundamental tradeoff in genomes and proteomes of prokaryotes established by the genetic code, codon entropy, and physics of nucleic acids and proteins.

Goncearenco, Alexander / Berezovsky, Igor N

Biology direct

2014 Volume 9, Page(s) 29

Abstract: Background: Mutations in nucleotide sequences provide a foundation for genetic variability, and selection is the driving force of the evolution and molecular adaptation. Despite considerable progress in the understanding of selective forces and their ... ...

Abstract	Background: Mutations in nucleotide sequences provide a foundation for genetic variability, and selection is the driving force of the evolution and molecular adaptation. Despite considerable progress in the understanding of selective forces and their compositional determinants, the very nature of underlying mutational biases remains unclear. Results: We explore here a fundamental tradeoff, which analytically describes mutual adjustment of the nucleotide and amino acid compositions and its possible effect on the mutational biases. The tradeoff is determined by the interplay between the genetic code, optimization of the codon entropy, and demands on the structure and stability of nucleic acids and proteins. Conclusion: The tradeoff is the unifying property of all prokaryotes regardless of the differences in their phylogenies, life styles, and extreme environments. It underlies mutational biases characteristic for genomes with different nucleotide and amino acid compositions, providing foundation for evolution and adaptation.
MeSH term(s)	Archaea/genetics ; Bacteria/genetics ; Base Composition ; Codon/genetics ; Entropy ; Genetic Code ; Genome ; Models, Genetic ; Mutation ; Proteome
Chemical Substances	Codon ; Proteome
Language	English
Publishing date	2014-12-12
Publishing country	England
Document type	Journal Article
ISSN	1745-6150
ISSN (online)	1745-6150
DOI	10.1186/s13062-014-0029-2
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Article ; Online: Molecular recognition of nucleosomes by binding partners.

Kale, Seyit / Goncearenco, Alexander / Markov, Yaroslav / Landsman, David / Panchenko, Anna R

Current opinion in structural biology

2019 Volume 56, Page(s) 164–170

Abstract: Nucleosomes represent the elementary units of chromatin packing and hubs in epigenetic signaling pathways. Across the chromatin and over the lifetime of the eukaryotic cell, nucleosomes experience a broad repertoire of alterations that affect their ... ...

Abstract	Nucleosomes represent the elementary units of chromatin packing and hubs in epigenetic signaling pathways. Across the chromatin and over the lifetime of the eukaryotic cell, nucleosomes experience a broad repertoire of alterations that affect their structure and binding with various chromatin factors. Dynamics of the histone core, nucleosomal and linker DNA, and intrinsic disorder of histone tails add further complexity to the nucleosome interaction landscape. In light of our understanding through the growing number of experimental and computational studies, we review the emerging patterns of molecular recognition of nucleosomes by their binding partners and assess the basic mechanisms of its regulation.
MeSH term(s)	Humans ; Intrinsically Disordered Proteins/metabolism ; Nucleosomes/metabolism
Chemical Substances	Intrinsically Disordered Proteins ; Nucleosomes
Language	English
Publishing date	2019-04-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Review
ZDB-ID	1068353-7
ISSN	1879-033X ; 0959-440X
ISSN (online)	1879-033X
ISSN	0959-440X
DOI	10.1016/j.sbi.2019.03.010
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