Annual Review of Biophysics 

About: Annual Review of Biophysics is an academic journal published by Annual Reviews. The journal publishes majorly in the area(s): Medicine & Biology. It has an ISSN identifier of 1936-122X. Over the lifetime, 349 publications have been published receiving 47532 citations.

Macromolecular Crowding and Confinement: Biochemical, Biophysical, and Potential Physiological Consequences*

Abstract: Expected and observed effects of volume exclusion on the free en- ergy of rigid and flexible macromolecules in crowded and confined systems, and consequent effects of crowding and confinement on macromolecular reaction rates and equilibria are summarized. Find- ings from relevant theoretical/simulation and experimental literature published from 2004 onward are reviewed. Additional complexity arising from the heterogeneity of local environments in biological media, and the presence of nonspecific interactions between macro- molecules over and above steric repulsion, are discussed. Theoretical and experimental approaches to the characterization of crowding- and confinement-induced effects in systems approaching the com- plexity of living organisms are suggested.

Intrinsically Disordered Proteins in Human Diseases: Introducing the D2 Concept

Abstract: Intrinsically disordered proteins (IDPs) lack stable tertiary and/or secondary structures under physiological conditions in vitro. They are highly abundant in nature and their functional repertoire complements the functions of ordered proteins. IDPs are involved in regulation, signaling, and control, where binding to multiple partners and high-specificity/low-affinity interactions play a crucial role. Functions of IDPs are tuned via alternative splicing and posttranslational modifications. Intrinsic disorder is a unique structural feature that enables IDPs to participate in both one-to-many and many-toone signaling. Numerous IDPs are associated with human diseases, including cancer, cardiovascular disease, amyloidoses, neurodegenerative diseases, and diabetes. Overall, intriguing interconnections among intrinsic disorder, cell signaling, and human diseases suggest that protein conformational diseases may result not only from protein misfolding, but also from misidentification, missignaling, and unnatural or nonnative folding. IDPs, such as α-synuclein, tau protein, p53, and BRCA1, are attractive targets for drugs modulating protein-protein interactions. From these and other examples, novel strategies for drug discovery based on IDPs have been developed. To summarize work in this area, we are introducing the D 2 (disorder in disorders) concept.

CRISPR-Cas9 Structures and Mechanisms.

Abstract: Many bacterial clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated (Cas) systems employ the dual RNA–guided DNA endonuclease Cas9 to defend against invading phages and conjugative plasmids by introducing site-specific double-stranded breaks in target DNA. Target recognition strictly requires the presence of a short protospacer adjacent motif (PAM) flanking the target site, and subsequent R-loop formation and strand scission are driven by complementary base pairing between the guide RNA and target DNA, Cas9–DNA interactions, and associated conformational changes. The use of CRISPR–Cas9 as an RNA-programmable DNA targeting and editing platform is simplified by a synthetic single-guide RNA (sgRNA) mimicking the natural dual trans-activating CRISPR RNA (tracrRNA)–CRISPR RNA (crRNA) structure. This review aims to provide an in-depth mechanistic and structural understanding of Cas9-mediated RNA-guided DNA targeting and cleavage. Molecular insights from biochemical and structural...

The Protein Folding Problem

Abstract: The “protein folding problem” consists of three closely related puzzles: (a) What is the folding code? (b) What is the folding mechanism? (c) Can we predict the native structure of a protein from its amino acid sequence? Once regarded as a grand challenge, protein folding has seen great progress in recent years. Now, foldable proteins and nonbiological polymers are being designed routinely and moving toward successful applications. The structures of small proteins are now often well predicted by computer methods. And, there is now a testable explanation for how a protein can fold so quickly: A protein solves its large global optimization problem as a series of smaller local optimization problems, growing and assembling the native structure from peptide fragments, local structures first.

Biomolecular Simulation: A Computational Microscope for Molecular Biology

Abstract: Molecular dynamics simulations capture the behavior of biological macromolecules in full atomic detail, but their computational demands, combined with the challenge of appropriately modeling the relevant physics, have historically restricted their length and accuracy. Dramatic recent improvements in achievable simulation speed and the underlying physical models have enabled atomic-level simulations on timescales as long as milliseconds that capture key biochemical processes such as protein folding, drug binding, membrane transport, and the conformational changes critical to protein function. Such simulation may serve as a computational microscope, revealing biomolecular mechanisms at spatial and temporal scales that are difficult to observe experimentally. We describe the rapidly evolving state of the art for atomic-level biomolecular simulation, illustrate the types of biological discoveries that can now be made through simulation, and discuss challenges motivating continued innovation in this field.