Geometry and symmetry presculpt the free-energy landscape of proteins

We present a simple physical model which demonstrates that the native state folds of proteins can emerge on the basis of considerations of geometry and symmetry. We show that the inherent anisotropy of a chain molecule, the geometrical and energetic constraints placed by the hydrogen bonds and sterics, and hydrophobicity are sufficient to yield a free energy landscape with broad minima even for a homopolymer. These minima correspond to marginally compact structures comprising the menu of folds that proteins choose from to house their native-states in. Our results provide a general framework for understanding the common characteristics of globular proteins.Comment: 23 pages, 5 figure

A database of immunoglobulins with integrated tools: DIGIT

The DIGIT (Database of ImmunoGlobulins with Integrated Tools) database (http://biocomputing.it/digit) is an integrated resource storing sequences of annotated immunoglobulin variable domains and enriched with tools for searching and analyzing them. The annotations in the database include information on the type of antigen, the respective germline sequences and on pairing information between light and heavy chains. Other annotations, such as the identification of the complementarity determining regions, assignment of their structural class and identification of mutations with respect to the germline, are computed on the fly and can also be obtained for user-submitted sequences. The system allows customized BLAST searches and automatic building of 3D models of the domains to be performed

Metastatic calcinosis cutis in a dialysis patient

Metastatic calcinosis cutis is an uncommon complication of end-stage kidney disease but has severe and disabling effects. Its development is attributed to disorders of calcium and phosphate metabolism associated with secondary hyperparathyroidism. The mainstay of treatment remains medical therapy; however, in refractory cases a parathyroidectomy is indicated. We describe the case of a 22-year-old female with refractory hyperparathyroidism treated with a subtotal parathyroidectomy resulting in complete resolution of metastatic calcinosis cutis of the hands. Clinicians should be aware that this complication can occur soon after the initiation of dialysis and that rapid complete resolution can be achieved with parathyroidectomy

A twist in chiral interaction between biological helices

Using an exact solution for the pair interaction potential, we show that long, rigid, chiral molecules with helical surface charge patterns have a preferential interaxial angle ~((RH)^1/2)/L, where L is the length of the molecules, R is the closest distance between their axes, and H is the helical pitch. Estimates based on this formula suggest a solution for the puzzle of small interaxial angles in a-helix bundles and in cholesteric phases of DNA.Comment: 7 pages, 2 figures, PDF file onl

Introduction to protein folding for physicists

The prediction of the three-dimensional native structure of proteins from the knowledge of their amino acid sequence, known as the protein folding problem, is one of the most important yet unsolved issues of modern science. Since the conformational behaviour of flexible molecules is nothing more than a complex physical problem, increasingly more physicists are moving into the study of protein systems, bringing with them powerful mathematical and computational tools, as well as the sharp intuition and deep images inherent to the physics discipline. This work attempts to facilitate the first steps of such a transition. In order to achieve this goal, we provide an exhaustive account of the reasons underlying the protein folding problem enormous relevance and summarize the present-day status of the methods aimed to solving it. We also provide an introduction to the particular structure of these biological heteropolymers, and we physically define the problem stating the assumptions behind this (commonly implicit) definition. Finally, we review the 'special flavor' of statistical mechanics that is typically used to study the astronomically large phase spaces of macromolecules. Throughout the whole work, much material that is found scattered in the literature has been put together here to improve comprehension and to serve as a handy reference.Comment: 53 pages, 18 figures, the figures are at a low resolution due to arXiv restrictions, for high-res figures, go to http://www.pabloechenique.co

Unfolding Rates for the Diffusion-Collision Model

In the diffusion-collision model, the unfolding rates are given by the likelihood of secondary structural cluster dissociation. In this work, we introduce an unfolding rate calculation for proteins whose secondary structural elements are $\alpha$-helices, modeled from thermal escape over a barrier which arises from the free energy in buried hydrophobic residues. Our results are in good agreement with currently accepted values for the attempt rate.Comment: Shorter version of cond-mat/0011024 accepted for publication in PR

The Origin of the Designability of Protein Structures

We examined what determines the designability of 2-letter codes (H and P) lattice proteins from three points of view. First, whether the native structure is searched within all possible structures or within maximally compact structures. Second, whether the structure of the used lattice is bipartite or not. Third, the effect of the length of the chain, namely, the number of monomers on the chain. We found that the bipartiteness of the lattice structure is not a main factor which determines the designability. Our results suggest that highly designable structures will be found when the length of the chain is sufficiently long to make the hydrophobic core consisting of enough number of monomers.Comment: 17 pages, 2 figure

Conformations of Proteins in Equilibrium

We introduce a simple theoretical approach for an equilibrium study of proteins with known native state structures. We test our approach with results on well-studied globular proteins, Chymotrypsin Inhibitor (2ci2), Barnase and the alpha spectrin SH3 domain and present evidence for a hierarchical onset of order on lowering the temperature with significant organization at the local level even at high temperatures. A further application to the folding process of HIV-1 protease shows that the model can be reliably used to identify key folding sites that are responsible for the development of drug resistance .Comment: 6 pages, 3 eps figure

POLYVIEW-MM: web-based platform for animation and analysis of molecular simulations

Molecular simulations offer important mechanistic and functional clues in studies of proteins and other macromolecules. However, interpreting the results of such simulations increasingly requires tools that can combine information from multiple structural databases and other web resources, and provide highly integrated and versatile analysis tools. Here, we present a new web server that integrates high-quality animation of molecular motion (MM) with structural and functional analysis of macromolecules. The new tool, dubbed POLYVIEW-MM, enables animation of trajectories generated by molecular dynamics and related simulation techniques, as well as visualization of alternative conformers, e.g. obtained as a result of protein structure prediction methods or small molecule docking. To facilitate structural analysis, POLYVIEW-MM combines interactive view and analysis of conformational changes using Jmol and its tailored extensions, publication quality animation using PyMol, and customizable 2D summary plots that provide an overview of MM, e.g. in terms of changes in secondary structure states and relative solvent accessibility of individual residues in proteins. Furthermore, POLYVIEW-MM integrates visualization with various structural annotations, including automated mapping of known inter-action sites from structural homologs, mapping of cavities and ligand binding sites, transmembrane regions and protein domains. URL: http://polyview.cchmc.org/conform.html

HIV and SARS-CoV-2 co-infection: The diagnostic challenges of dual pandemics

The first critically ill patient admitted to our hospital in Cape Town, South Africa, during the COVID-19 pandemic was co-infected with HIV and SARS-CoV-2. Pneumocystis jirovecii pneumonia (PCP) and other respiratory opportunistic infections share many clinical features with severe COVID-19. Our understanding of the nuances of co-management of HIV and COVID-19 is evolving. We describe the diagnostic and therapeutic challenges presented by this case