Biophysical Reviews: a transition in the journal.

This Editorial for Volume 16 Issue 2 first describes the issue contents before describing some upcoming events within Biophysical Reviews and concludies with an announcement on the transition of Chief Editors thanks to the outgoing Chief Editor.

Biophysical reviews Special issue call: The 21st IUPAB Congress 2024 Kyoto Japan.

This commentary describes an open call for submissions to the upcoming Biophysical Reviews' Special Issue: The 21st IUPAB Congress 2024 Kyoto Japan. The submission deadline is July 1st of 2024. Interested parties are requested to make contact with the Special Issue editors prior to submission.

Editors' roundup: October 2022.

This commentary constitutes the October edition of the 'Editors' roundup'-a multi-author omnibus of personal recommendations to interesting biophysics-related articles contributed by members of the editorial boards of leading international biophysics journals. The present commentary contains contributions from Progress in Biochemistry and Biophysics (an official journal of the Biophysical Society of China), European Biophysics Journal (the official journal of the European Biophysical Societies Association), Biophysical Reviews (the official IUPAB journal), and Biophysics (an official journal of the Russian Academy of Sciences). This edition of the Editors' Roundup also contains a new section from an editor at large who has provided selections from a number of journals on a single thematic topic.

Insights into DNA solvation found in protein-DNA structures.

The proteins that bind double-helical DNA present various microenvironments that sense and/or induce signals in the genetic material. The high-resolution structures of protein-DNA complexes reveal the nature of both the microenvironments and the conformational responses in DNA and protein. Complex networks of interactions within the structures somehow tie the protein and DNA together and induce the observed spatial forms. Here we show how the cumulative buildup of amino acid atoms around the sugars, phosphates, and bases in different protein-DNA complexes produces a binding cloud around the double helix and how different types of atoms fill that cloud. Rather than focusing on the principles of molecular binding and recognition suggested by the arrangements of amino acids and nucleotides in the macromolecular complexes, we consider the proteins in contact with DNA as organized solvents. We describe differences in the mix of atoms that come in closest contact with DNA, subtle sequence-dependent features in the microenvironment of the sugar-phosphate backbone, a direct link between the localized buildup of ionic species and the electrostatic potential surfaces of the DNA bases, and sites of atomic buildup above and below the basepair planes that transmit the unique features of the base environments along the chain backbone. The inferences about solvation that can be drawn from the survey provide new stimuli for improvement of nucleic acid force fields and fresh ideas for exploration of the properties of DNA in solution.

Revisiting DNA Sequence-Dependent Deformability in High-Resolution Structures: Effects of Flanking Base Pairs on Dinucleotide Morphology and Global Chain Configuration.

DNA carries more than the list of biochemical ingredients that drive the basic functions of living systems. The sequence of base pairs includes a multitude of structural and energetic signals, which determine the degree to which the long, threadlike molecule moves and how it responds to proteins and other molecules that control its processing and govern its packaging. The chemical composition of base pairs directs the spatial disposition and fluctuations of successive residues. The observed arrangements of these moieties in high-resolution protein-DNA crystal structures provide one of the best available estimates of the natural, sequence-dependent structure and deformability of the double-helical molecule. Here, we update the set of knowledge-based elastic potentials designed to describe the observed equilibrium structures and configurational fluctuations of the ten unique base-pair steps. The large number of currently available structures makes it possible to characterize the configurational preferences of the DNA base-pair steps within the context of their immediate neighbors, i.e., tetrameric context. Use of these knowledge-based potentials shows promise in accounting for known effects of sequence in long chain molecules, e.g., the degree of curvature reported in classic gel mobility studies and the recently reported sequence-dependent responses of supercoiled minicircles to nuclease cleavage.

emDNA - A Tool for Modeling Protein-decorated DNA Loops and Minicircles at the Base-pair Step Level.

Computational modeling of nucleic acids plays an important role in molecular biology, enhancing our general understanding of the relationship between structure and function. Biophysical studies have provided a wealth of information on how double-helical DNA responds to proteins and other molecules in its local environment but far less understanding of the larger scale structural responses found in protein-decorated loops and minicircles. Current computational models of DNA range from detailed all-atom molecular dynamics studies, which produce rich time and spatially dependent depictions of small DNA fragments, to coarse-grained simulations, which sacrifice detailed physical and chemical information to treat larger-scale systems. The treatment of DNA used here, at the base-pair step level with rigid-body parameters, allows one to develop models hundreds of base pairs long from local, sequence-specific features found from experiment. The emDNA software takes advantage of this framework, producing optimized structures of DNA at thermal equilibrium with built-in or user-generated elastic models. The program, in combination with the case studies included in this article, allows users of any skill level to develop and investigate mesoscale models of their own design. The functionality of emDNA includes a tool to incorporate experiment-specific configurations, e.g., protein-bound and/or melted DNA from known high-resolution structures, within higher-order 3D models by fixing the orientation and position of user-specified base pairs. The software provides a new avenue into multiscale genetic modeling, giving a wide range of users a deeper understanding of DNA mesoscale organization and the opportunity to pose new questions in genetic research. The publicly available emDNA software, including build instructions and usage information, is available on GitHub (https://nicocvn.github.io/emDNA/).

Designed architectural proteins that tune DNA looping in bacteria.

Architectural proteins alter the shape of DNA. Some distort the double helix by introducing sharp kinks. This can serve to relieve strain in tightly-bent DNA structures. Here, we design and test artificial architectural proteins based on a sequence-specific Transcription Activator-like Effector (TALE) protein, either alone or fused to a eukaryotic high mobility group B (HMGB) DNA-bending domain. We hypothesized that TALE protein binding would stiffen DNA to bending and twisting, acting as an architectural protein that antagonizes the formation of small DNA loops. In contrast, fusion to an HMGB domain was hypothesized to generate a targeted DNA-bending architectural protein that facilitates DNA looping. We provide evidence from Escherichia coli Lac repressor gene regulatory loops supporting these hypotheses in living bacteria. Both data fitting to a thermodynamic DNA looping model and sophisticated molecular modeling support the interpretation of these results. We find that TALE protein binding inhibits looping by stiffening DNA to bending and twisting, while the Nhp6A domain enhances looping by bending DNA without introducing twisting flexibility. Our work illustrates artificial approaches to sculpt DNA geometry with functional consequences. Similar approaches may be applicable to tune the stability of small DNA loops in eukaryotes.

Surprising Twists in Nucleosomal DNA with Implication for Higher-order Folding.

While nucleosomes are dynamic entities that must undergo structural deformations to perform their functions, the general view from available high-resolution structures is a largely static one. Even though numerous examples of twist defects have been documented, the DNA wrapped around the histone core is generally thought to be overtwisted. Analysis of available high-resolution structures from the Protein Data Bank reveals a heterogeneous distribution of twist along the nucleosomal DNA, with clear patterns that are consistent with the literature, and a significant fraction of structures that are undertwisted. The subtle differences in nucleosomal DNA folding, which extend beyond twist, have implications for nucleosome disassembly and modeled higher-order structures. Simulations of oligonucleosome arrays built with undertwisted models behave very differently from those constructed from overtwisted models, in terms of compaction and inter-nucleosome contacts, introducing configurational changes equivalent to those associated with 2-3 base-pair changes in nucleosome spacing. Differences in the nucleosomal DNA pathway, which underlie the way that DNA enters and exits the nucleosome, give rise to different nucleosome-decorated minicircles and affect the topological mix of configurational states.

Synergy between Protein Positioning and DNA Elasticity: Energy Minimization of Protein-Decorated DNA Minicircles.

The binding of proteins onto DNA contributes to the shaping and packaging of the genome as well as to the expression of specific genetic messages. With a view to understanding the interplay between the presence of proteins and the deformation of DNA involved in such processes, we developed a new method to minimize the elastic energy of DNA fragments at the mesoscale level. Our method makes it possible to obtain the optimal pathways of protein-decorated DNA molecules for which the terminal base pairs are spatially constrained. We focus in this work on the deformations induced by selected architectural proteins on circular DNA. We report the energy landscapes of DNA minicircles subjected to different levels of torsional stress and containing one or two proteins as functions of the chain length and spacing between the proteins. Our results reveal cooperation between the elasticity of the double helix and the structural distortions of DNA induced by bound proteins. We find that the imposed mechanical stress influences the placement of proteins on DNA and that the proteins, in turn, modulate the mechanical stress and thereby broadcast their presence along DNA.

Biophysical Reviews' "Meet the Editors Series"-a profile of Wilma K. Olson.

As one of the five Executive Editors of Biophysical Reviews I have been asked to provide this short biographical sketch for the readers of the journal. I have been a member of the Editorial Board since the inception of the journal in 2008 and an Executive Editor since 2014. I hold a B.S. degree in Chemistry from the University of Delaware and a Ph.D. in Physical Chemistry from Stanford University. Except for a year as a Damon Runyon Postdoctoral Fellow at Columbia University, I have spent my entire professional career at Rutgers, the State University of New Jersey, where I am currently the Mary I. Bunting Professor of Chemistry and Chemical Biology. I served for many years as Founding Director of the Rutgers University Center for Molecular Biophysics and Biophysical Chemistry, and have trained undergraduate, graduate, and postdoctoral students from a variety of academic disciplines.

An analytical method to connect open curves for modeling protein-bound DNA minicircles.

We introduce an analytical method to generate the pathway of a closed protein-bound DNA minicircle. We develop an analytical equation to connect two open curves smoothly and use the derived expressions to join the ends of two helical pathways and form models of nucleosome-decorated DNA minicircles. We find that the simplest smooth connector which satisfies the boundary conditions at the end points and the length requirement for such connections to be a quartic function on the xy-plane and linear along the z-direction. This is a general method which can be used to connect any two open curves with well defined mathematical definitions as well as pairs of discrete systems found experimentally. We used this method to describe the configurations of torsionally relaxed, 360-base pair DNA rings with two evenly-spaced, ideal nucleosomes. We considered superhelical nucleosomal pathways with different levels of DNA wrapping and allowed for different inter-nucleosome orientations. We completed the DNA circles with the smooth connectors and studied the associated bending and electrostatic energies for different configurations in the absence and presence of salt. The predicted stable states bear close resemblance to reconstituted minicircles observed under low and high salt conditions.

Web 3DNA 2.0 for the analysis, visualization, and modeling of 3D nucleic acid structures.

Web 3DNA (w3DNA) 2.0 is a significantly enhanced version of the widely used w3DNA server for the analysis, visualization, and modeling of 3D nucleic-acid-containing structures. Since its initial release in 2009, the w3DNA server has continuously served the community by making commonly-used features of the 3DNA suite of command-line programs readily accessible. However, due to the lack of updates, w3DNA has clearly shown its age in terms of modern web technologies and it has long lagged behind further developments of 3DNA per se. The w3DNA 2.0 server presented here overcomes all known shortcomings of w3DNA while maintaining its battle-tested characteristics. Technically, w3DNA 2.0 implements a simple and intuitive interface (with sensible defaults) for increased usability, and it complies with HTML5 web standards for broad accessibility. Featurewise, w3DNA 2.0 employs the most recent version of 3DNA, enhanced with many new functionalities, including: the automatic handling of modified nucleotides; a set of 'simple' base-pair and step parameters for qualitative characterization of non-Watson-Crick double-helical structures; new structural parameters that integrate the rigid base plane and the backbone phosphate group, the two nucleic acid components most reliably determined with X-ray crystallography; in silico base mutations that preserve the backbone geometry; and a notably improved module for building models of single-stranded RNA, double-helical DNA, Pauling triplex, G-quadruplex, or DNA structures 'decorated' with proteins. The w3DNA 2.0 server is freely available, without registration, at http://web.x3dna.org.

Computational Simulation of Adapter Length-Dependent LASSO Probe Capture Efficiency.

Multiplexed cloning of long DNA sequences is a valuable technique in many biotechnology applications, such as long-read genome sequencing and the creation of open reading frame (ORF) libraries. Long-adapter single-stranded oligonucleotide (LASSO) probes have shown promise as a tool to clone long DNA fragments. LASSO probes are molecular inversion probes (MIP) engineered with an adapter region of user-defined length, flanked between template-specific probe sequences. Herein, we demonstrate that the adapter length is a key feature of LASSO that influences the efficiency of gene capture and cloning. Furthermore, we applied a model based on Monte Carlo molecular simulation in order to study the relationship between the long-adapter length of LASSO and capture enrichment. Our results suggest that the adapter length is a factor that contributes to the free energy of target-probe interaction, thereby determining the efficiency of capture. The results indicate that LASSOs with extremely long adapters cannot capture the targets well. They also suggest that targets of different lengths may prefer adapters of different lengths.

Effects of Noncanonical Base Pairing on RNA Folding: Structural Context and Spatial Arrangements of G·A Pairs.

Noncanonical base pairs play important roles in assembling the three-dimensional structures critical to the diverse functions of RNA. These associations contribute to the looped segments that intersperse the canonical double-helical elements within folded, globular RNA molecules. They stitch together various structural elements, serve as recognition elements for other molecules, and act as sites of intrinsic stiffness or deformability. This work takes advantage of new software (DSSR) designed to streamline the analysis and annotation of RNA three-dimensional structures. The multiscale structural information gathered for individual molecules, combined with the growing number of unique, well-resolved RNA structures, makes it possible to examine the collective features deeply and to uncover previously unrecognized patterns of chain organization. Here we focus on a subset of noncanonical base pairs involving guanine and adenine and the links between their modes of association, secondary structural context, and contributions to tertiary folding. The rigorous descriptions of base-pair geometry that we employ facilitate characterization of recurrent geometric motifs and the structural settings in which these arrangements occur. Moreover, the numerical parameters hint at the natural motions of the interacting bases and the pathways likely to connect different spatial forms. We draw attention to higher-order multiplexes involving two or more G·A pairs and the roles these associations appear to play in bridging different secondary structural units. The collective data reveal pairing propensities in base organization, secondary structural context, and deformability and serve as a starting point for further multiscale investigations and/or simulations of RNA folding.

Toward a Universal Structural and Energetic Model for Prokaryotic Promoters.

With almost no consensus promoter sequence in prokaryotes, recruitment of RNA polymerase (RNAP) to precise transcriptional start sites (TSSs) has remained an unsolved puzzle. Uncovering the underlying mechanism is critical for understanding the principle of gene regulation. We attempted to search the hidden code in ∼16,500 promoters of 12 prokaryotes representing two kingdoms in their structure and energetics. Twenty-eight fundamental parameters of DNA structure including backbone angles, basepair axis, and interbasepair and intrabasepair parameters were used, and information was extracted from x-ray crystallography data. Three parameters (solvation energy, hydrogen-bond energy, and stacking energy) were selected for creating energetics profiles using in-house programs. DNA of promoter regions was found to be inherently designed to undergo a change in every parameter undertaken for the study, in all prokaryotes. The change starts from some distance upstream of TSSs and continues past some distance from TSS, hence giving a signature state to promoter regions. These signature states might be the universal hidden codes recognized by RNAP. This observation was reiterated when randomly selected promoter sequences (with little sequence conservation) were subjected to structure generation; all developed into very similar three-dimensional structures quite distinct from those of conventional B-DNA and coding sequences. Fine structural details at important motifs (viz. -11, -35, and -75 positions relative to TSS) of promoters reveal novel to our knowledge and pointed insights for RNAP interaction at these locations; it could be correlated with how some particular structural changes at the -11 region may allow insertion of RNAP amino acids in interbasepair space as well as facilitate the flipping out of bases from the DNA duplex.

Parallels between DNA and collagen - comparing elastic models of the double and triple helix.

Multi-stranded helices are widespread in nature. The interplay of polymeric properties with biological function is seldom discussed. This study probes analogies between structural and mechanical properties of collagen and DNA. We modeled collagen with Eulerian rotational and translational parameters of adjacent rungs in the triple-helix ladder and developed statistical potentials by extracting the dispersion of the parameters from a database of atomic-resolution structures. The resulting elastic model provides a common quantitative way to describe collagen deformations upon interacting with integrins or matrix metalloproteinase and DNA deformations upon protein binding. On a larger scale, deformations in Type I collagen vary with a periodicity consistent with the D-periodic banding of higher-order fibers assemblies. This indicates that morphologies of natural higher-order collagen packing might be rooted in the characteristic deformation patterns.

Towards quantitative analysis of gene regulation by enhancers.

Enhancers are regulatory DNA sequences that can activate transcription over large distances. Recent studies have revealed the widespread role of distant activation in eukaryotic gene regulation and in the development of various human diseases, including cancer. Here we review recent progress in the field, focusing on new experimental and computational approaches that quantify the role of chromatin structure and dynamics during enhancer-promoter interactions in vitro and in vivo.

Nucleosome-free DNA regions differentially affect distant communication in chromatin.

Communication between distantly spaced genomic regions is one of the key features of gene regulation in eukaryotes. Chromatin per se can stimulate efficient enhancer-promoter communication (EPC); however, the role of chromatin structure and dynamics in this process remains poorly understood. Here we show that nucleosome spacing and the presence of nucleosome-free DNA regions can modulate chromatin structure/dynamics and, in turn, affect the rate of EPC in vitro and in silico. Increasing the length of internucleosomal linker DNA from 25 to 60 bp results in more efficient EPC. The presence of longer nucleosome-free DNA regions can positively or negatively affect the rate of EPC, depending upon the length and location of the DNA region within the chromatin fiber. Thus the presence of histone-free DNA regions can differentially affect the efficiency of EPC, suggesting that gene regulation over a distance could be modulated by changes in the length of internucleosomal DNA spacers.

Contributions of Sequence to the Higher-Order Structures of DNA.

One of the critical unanswered questions in genome biophysics is how the primary sequence of DNA bases influences the global properties of very-long-chain molecules. The local sequence-dependent features of DNA found in high-resolution structures introduce irregularities in the disposition of adjacent residues that facilitate the specific binding of proteins and modulate the global folding and interactions of double helices with hundreds of basepairs. These features also determine the positions of nucleosomes on DNA and the lengths of the interspersed DNA linkers. Like the patterns of basepair association within DNA, the arrangements of nucleosomes in chromatin modulate the properties of longer polymers. The intrachromosomal loops detected in genomic studies contain hundreds of nucleosomes, and given that the simulated configurations of chromatin depend on the lengths of linker DNA, the formation of these loops may reflect sequence-dependent information encoded within the positioning of the nucleosomes. With knowledge of the positions of nucleosomes on a given genome, methods are now at hand to estimate the looping propensities of chromatin in terms of the spacing of nucleosomes and to make a direct connection between the DNA base sequence and larger-scale chromatin folding.