A gyökfogó dokozahexaénsav mint agyvédő = Docosahexaenoic acid (DHA) as a free radical scavenger brain protector

Telítetlen zsírsavak (PUFA) fontos szerepet játszanak mint antioxidánsok az emberi testben, különös tekintettel az agyban. Lipidek szisztematikus számítási vizsgálatait az OTKA támogatás előtt már elkezdtük. A támogatás alatt 4 fő tématerületen értünk el eredményeket: Téma 1: Molekuláris konformció változások termodinamikai alapjai Egyszerű szerves molekulák, mint különböző szénhidrogén származékok, peptidek, folytonos termodinamikai fügvényeit állítottuk elő konformációs mozgások mentén. Téma 2: Zsirsavak konformációs információ Igazoltuk a PUFA-k flexibilátásbeli hasonlóságát a peptidekhez a potenciál felületek hasonlóságával. DHA a legfontosabb képviselője a PUFA családnak. Téma 3: Foszfolipidek konformációs információi Az első két téma eredmnyeinek felhasználásával egyszerű foszfolipid modelleket konstruáltunk. A két zsirsavlánc relativ helyzte, kölcsönhatásai, membránszerű elrendeződés esetén állt vizsgálataink homlokterében. Téma4 Szabadgyökök reakciói PUFA és PUFA modellekkel Szabadgyökök és reakcióik PUFA-val lipidek kettősrétegeiben biológiailag nagyon fontos folyamatok. Az E vitamin az egyik leghatékonyabb gyökfogó membránokban. A PUFA-kban mindig megtalálható allil-C-H kötések és különböző típusú gyökök reakcióinak kiterjedt vizsgálata folyt. | Polyunsaturated fatty acids (PUFA) play an important role as an antioxidant in the whole human body but more specifically in the brain. The overall project had 4 Topics: Topic 1 Fundamental Thermodynamics of Molecular Conformational Changes: Simple organic molecules were investigated in computing continues thermodynamic functions along conformational changes. These included a variety of compounds from hydrocarbons to peptides. Topic 2 Conformational information of fatty acid: Interestingly enough their felxibility was similar to that of peptides as could be judged from the similarity of their conformational potential energy surfaces. Topic 3 Conformational information of phospholipids: The results and experience obtained from the first two topics were used to construct simple phospholipids. The relative orientations of the two fatty acids in a phospholipid had to be studied to see if the nearly parallel arrangement within the lipid bilayer is enforced by nearest neighbour interaction or if such a geometry is an intrinsically stable structure. Topic 4 Free radical reactions with PUFA and PUFA models: Free radicals and their reactions with PUFA within the lipid bilayer are a biologically very important reactions. The generation of free radicals and their transformation as well as their reactions with allylic C-H bonds, which are always present is PUFA, has been studied in details

Confinement Effects on the Kinetics and Thermodynamics of Protein Dimerization

In the cell, protein complexes form relying on specific interactions between their monomers. Excluded volume effects due to molecular crowding would lead to correlations between molecules even without specific interactions. What is the interplay of these effects in the crowded cellular environment? We study dimerization of a model homodimer both when the mondimers are free or tethered to each other. We consider a structured environment: Two monomers first diffuse into a cavity of size $L$ and then fold and bind within the cavity. The folding and binding are simulated using molecular dynamics based on a simplified topology based model. The {\it confinement} in the cell is described by an effective molecular concentration $C \sim L^{-3}$. A two-state coupled folding and binding behavior is found. We show the maximal rate of dimerization occurred at an effective molecular concentration $C^{op}\simeq 1m$M which is a relevant cellular concentration. In contrast, for tethered chains the rate keeps at a plateau when $CC^{op}$. For both the free and tethered cases, the simulated variation of the rate of dimerization and thermodynamic stability with effective molecular concentration agrees well with experimental observations. In addition, a theoretical argument for the effects of confinement on dimerization is also made

Macromolecular structural dynamics visualized by pulsed dose control in 4D electron microscopy

Macromolecular conformation dynamics, which span a wide range of time scales, are fundamental to the understanding of properties and functions of their structures. Here, we report direct imaging of structural dynamics of helical macromolecules over the time scales of conformational dynamics (ns to subsecond) by means of four-dimensional (4D) electron microscopy in the single-pulse and stroboscopic modes. With temporally controlled electron dosage, both diffraction and real-space images are obtained without irreversible radiation damage. In this way, the order-disorder transition is revealed for the organic chain polymer. Through a series of equilibrium-temperature and temperature-jump dependencies, it is shown that the metastable structures and entropy of conformations can be mapped in the nonequilibrium region of a “funnel-like” free-energy landscape. The T-jump is introduced through a substrate (a “hot plate” type arrangement) because only the substrate is made to absorb the pulsed energy. These results illustrate the promise of ultrafast 4D imaging for other applications in the study of polymer physics as well as in the visualization of biological phenomena

Disordered proteins and network disorder in network descriptions of protein structure, dynamics and function. Hypotheses and a comprehensive review

During the last decade, network approaches became a powerful tool to describe protein structure and dynamics. Here we review the links between disordered proteins and the associated networks, and describe the consequences of local, mesoscopic and global network disorder on changes in protein structure and dynamics. We introduce a new classification of protein networks into ‘cumulus-type’, i.e., those similar to puffy (white) clouds, and ‘stratus-type’, i.e., those similar to flat, dense (dark) low-lying clouds, and relate these network types to protein disorder dynamics and to differences in energy transmission processes. In the first class, there is limited overlap between the modules, which implies higher rigidity of the individual units; there the conformational changes can be described by an ‘energy transfer’ mechanism. In the second class, the topology presents a compact structure with significant overlap between the modules; there the conformational changes can be described by ‘multi-trajectories’; that is, multiple highly populated pathways. We further propose that disordered protein regions evolved to help other protein segments reach ‘rarely visited’ but functionally-related states. We also show the role of disorder in ‘spatial games’ of amino acids; highlight the effects of intrinsically disordered proteins (IDPs) on cellular networks and list some possible studies linking protein disorder and protein structure networks

Folding of small disulfide-rich proteins : clarifying the puzzle

Premi a l'excel·lència investigadora. Àmbit de les Ciències Experimentals. 2008The process by which small proteins fold to their native conformations has been intensively studied over the last few decades. In this field, the particular chemistry of disulfide bond formation has facilitated the characterization of the oxidative folding of numerous small, disulfide-rich proteins with results that illustrate a high diversity of folding mechanisms, differing in the heterogeneity and disulfide pairing nativeness of their intermediates. In this review, we combine information on the folding of different protein models together with the recent structural determinations of major intermediates to provide new molecular clues in oxidative folding. Also, we turn to analyze the role of disulfide bonds in misfolding and protein aggregation and their implications in amyloidosis and conformational diseases

Frustration in Biomolecules

Biomolecules are the prime information processing elements of living matter. Most of these inanimate systems are polymers that compute their structures and dynamics using as input seemingly random character strings of their sequence, following which they coalesce and perform integrated cellular functions. In large computational systems with a finite interaction-codes, the appearance of conflicting goals is inevitable. Simple conflicting forces can lead to quite complex structures and behaviors, leading to the concept of "frustration" in condensed matter. We present here some basic ideas about frustration in biomolecules and how the frustration concept leads to a better appreciation of many aspects of the architecture of biomolecules, and how structure connects to function. These ideas are simultaneously both seductively simple and perilously subtle to grasp completely. The energy landscape theory of protein folding provides a framework for quantifying frustration in large systems and has been implemented at many levels of description. We first review the notion of frustration from the areas of abstract logic and its uses in simple condensed matter systems. We discuss then how the frustration concept applies specifically to heteropolymers, testing folding landscape theory in computer simulations of protein models and in experimentally accessible systems. Studying the aspects of frustration averaged over many proteins provides ways to infer energy functions useful for reliable structure prediction. We discuss how frustration affects folding, how a large part of the biological functions of proteins are related to subtle local frustration effects and how frustration influences the appearance of metastable states, the nature of binding processes, catalysis and allosteric transitions. We hope to illustrate how Frustration is a fundamental concept in relating function to structural biology.Comment: 97 pages, 30 figure

Capturing the essence of folding and functions of biomolecules using Coarse-Grained Models

The distances over which biological molecules and their complexes can function range from a few nanometres, in the case of folded structures, to millimetres, for example during chromosome organization. Describing phenomena that cover such diverse length, and also time scales, requires models that capture the underlying physics for the particular length scale of interest. Theoretical ideas, in particular, concepts from polymer physics, have guided the development of coarse-grained models to study folding of DNA, RNA, and proteins. More recently, such models and their variants have been applied to the functions of biological nanomachines. Simulations using coarse-grained models are now poised to address a wide range of problems in biology.Comment: 37 pages, 8 figure