scholarly journals Influence of spatial structure on protein damage susceptibility – A bioinformatics approach

2020 ◽  
Author(s):  
Maximilian Fichtner ◽  
Stefan Schuster ◽  
Heiko Stark

AbstractAging research is a very popular field of research in which the gradual transformation of functional states into dysfunctional states are studied. Here we only consider the molecular level, which can also have effects on the macroscopic level. It is known that the proteinogenic amino acids differ in their modification susceptibilities and this can affect the function of proteins. For this it is important to know the distribution of amino acids between the protein surface/shell and the core. This was investigated in this study for all known structural data of peptides and proteins. As a result it is shown that the surface contains less susceptible amino acids than the core with the exception of thermophilic organisms. Furthermore, proteins could be classified according to their susceptibility. This can then be used in applications such as phylogeny, aging research, molecular medicine and synthetic biology.

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maximilian Fichtner ◽  
Stefan Schuster ◽  
Heiko Stark

AbstractAging research is a very popular field of research in which the deterioration or decline of various physiological features is studied. Here we consider the molecular level, which can also have effects on the macroscopic level. The proteinogenic amino acids differ in their susceptibilities to non-enzymatic modification. Some of these modifications can lead to protein damage and thus can affect the form and function of proteins. For this, it is important to know the distribution of amino acids between the protein shell/surface and the core. This was investigated in this study for all known structures of peptides and proteins available in the PDB. As a result, it is shown that the shell contains less susceptible amino acids than the core with the exception of thermophilic organisms. Furthermore, proteins could be classified according to their susceptibility. This can then be used in applications such as phylogeny, aging research, molecular medicine, and synthetic biology.


Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1167
Author(s):  
Manjinder S. Cheema ◽  
Katrina V. Good ◽  
Bohyun Kim ◽  
Heddy Soufari ◽  
Connor O’Sullivan ◽  
...  

The replication independent (RI) histone H2A.Z is one of the more extensively studied variant members of the core histone H2A family, which consists of many replication dependent (RD) members. The protein has been shown to be indispensable for survival, and involved in multiple roles from DNA damage to chromosome segregation, replication, and transcription. However, its functional involvement in gene expression is controversial. Moreover, the variant in several groups of metazoan organisms consists of two main isoforms (H2A.Z-1 and H2A.Z-2) that differ in a few (3–6) amino acids. They comprise the main topic of this review, starting from the events that led to their identification, what is currently known about them, followed by further experimental, structural, and functional insight into their roles. Despite their structural differences, a direct correlation to their functional variability remains enigmatic. As all of this is being elucidated, it appears that a strong functional involvement of isoform variability may be connected to development.


2017 ◽  
Author(s):  
Rebecca F. Alford ◽  
Andrew Leaver-Fay ◽  
Jeliazko R. Jeliazkov ◽  
Matthew J. O'Meara ◽  
Frank P. DiMaio ◽  
...  

AbstractOver the past decade, the Rosetta biomolecular modeling suite has informed diverse biological questions and engineering challenges ranging from interpretation of low-resolution structural data to design of nanomaterials, protein therapeutics, and vaccines. Central to Rosetta’s success is the energy function: amodel parameterized from small molecule and X-ray crystal structure data used to approximate the energy associated with each biomolecule conformation. This paper describes the mathematical models and physical concepts that underlie the latest Rosetta energy function, beta_nov15. Applying these concepts,we explain how to use Rosetta energies to identify and analyze the features of biomolecular models.Finally, we discuss the latest advances in the energy function that extend capabilities from soluble proteins to also include membrane proteins, peptides containing non-canonical amino acids, carbohydrates, nucleic acids, and other macromolecules.


Author(s):  
Gary W. Morrow

We have already seen that some of the basic building blocks used in the biosynthesis of natural products are amino acids such as phenylalanine, tyrosine, and others. These and other crucial construction materials such as the acyl group in acetyl-CoA are all ultimately derived from carbohydrates. In this chapter, we will present an abbreviated overview of the components of carbohydrate structure and metabolism sufficient for our purposes going forward, with a schematic flowchart showing how carbohydrates and amino acids are modified, combined, and branched off in various ways to yield the distinct set of biosynthetic pathways that will form the core of the remainder of the text. We will finish the chapter with a brief, general review of amino acid nomenclature and structure with emphasis on the key amino acids that will be used throughout the remainder of the text. We know that plants make glucose (C6H12O6) by photosynthesis using light, water (H2O), and carbon dioxide (CO2). Another way of looking at the formula for glucose is C6(H2O)6, that is, six carbon atoms and six water molecules. Thus, glucose was originally referred to as a hydrated form of carbon—a carbohydrate. But this is a very general term since there are many different types of carbohydrate compounds. One way to broadly classify carbohydrates is to identify them as either mono- (one), di- (two), oligo- (a few) or poly- (many) saccharides. For example, glucose (C6H12O6) cannot be broken down into simpler carbohydrates by simple hydrolysis, so it is classified as a monosaccharide, that is, a single, discrete carbohydrate compound. On the other hand, the carbohydrate sucrose (C12H22O11) is classified as a disaccharide since when it is subjected to aqueous hydrolysis, it yields two different monosaccharide carbohydrates, namely glucose (C6H12O6) and fructose (C6H12O6). Noting that glucose and fructose are different compounds but with the same molecular formula, they must be related to one another either as stereoisomers or as constitutional isomers, so further refinement of classification is needed. Structurally speaking, most monosaccharide carbohydrates are simply polyhydroxyaldehydes (aldoses) or polyhydroxyketones (ketoses) which can be further classified using a combination of aldo- or keto- prefixes along with suffixes such as triose, tetrose, pentose, or hexose to designate the number of carbon atoms.


1994 ◽  
Vol 49 (9-10) ◽  
pp. 571-578 ◽  
Author(s):  
J. Sivý ◽  
V. Kettmann ◽  
J. Krätsmár-Šmogrovič

Abstract The crystal structure of [(N-salicylidene-ᴅ,ʟ-glutamato)(pyridine)]copper(II), a model for vitamin B6-amino acid-related metal complexes, has been determined by an X-ray analysis. A close examination of the structural data on this and other related complexes combined with quantum-chemical (INDO/2) calculations enabled us to make a clear distinction between two mechanisms proposed earlier for metabolic reactions of amino acids catalyzed by the vitamin B6 (or salicylaldehyde)-metal system. The results are consistent with a transient formation of a carbinolamine species resulting from the addition of a solvent water or alcohol molecule to the Schiff base double bond, thus supporting the mechanism of the catalysis as proposed by Gillard and Wootton.


2013 ◽  
Vol 189 (1) ◽  
pp. 221-227 ◽  
Author(s):  
Kenichi Tadokoro ◽  
Mariko Kobayashi ◽  
Fumitaka Suzuki ◽  
Chie Tanaka ◽  
Toshikazu Yamaguchi ◽  
...  

2014 ◽  
Vol 88 (18) ◽  
pp. 10738-10747 ◽  
Author(s):  
J. May ◽  
P. Viswanathan ◽  
K. K.- S. Ng ◽  
A. Medvedev ◽  
B. Korba

2019 ◽  
Vol 57 (3) ◽  
pp. 33-41
Author(s):  
Boris A. Markov ◽  
◽  
Yury I. Sukharev ◽  

We obtained two equations that characterize the structure of the colloid: the equation of the Schrodinger type that specifies the redistribution of heat and potential energy in the colloid and material equation – the diffusion equation with the operator of Liesegang associated directly with a substance that allows you to find the discontinuities of the structures caused by the vibrations of electrically charged particles. This procedure based on the assumption of the instability of the colloidal state, caused by the movement of charged particles. The reality is not collected in parts from the particles of matter in the course of evolution from the past to the future, and is all at once from the past to the future for a given pattern, that is, for specific PATTERNS, as defined by quantum theory. Without going deep into the theory of Kulakov, we will accept its fundamental provisions as a certain given. The forms of this structural data were obtained experimentally and mathematically confirmed. Let there be a certain angle of the skeleton, where due to the unevenness and partial randomness of the structure of the core grids forms "defects" – that is, electrical or magnetic moments of a particular order. Then small mobile clusters are attracted to it by electrostatic or electromagnetic forces, which are then adsorbed and somehow arranged on the "defects" in accordance with their dipole moments. This circumstance can be determined by "magic numbers", that is, as the number of clusters "stuck" to the defect of the core structure, with the formation of chemical bonds in the future. We can assume that the spanning structure of Coxeter can form small clusters form regular polyhedrons, and may occur or other structure having more complicated form.


2021 ◽  
Author(s):  
Marta Alenquer ◽  
Filipe Ferreira ◽  
Diana Lousa ◽  
Mariana Valério ◽  
Mónica Medina-Lopes ◽  
...  

AbstractUnderstanding SARS-CoV-2 evolution and host immunity is critical to control COVID-19 pandemics. At the core is an arms-race between SARS-CoV-2 antibody and angiotensin-converting enzyme 2 (ACE2) recognition, a function of the viral protein spike and, predominantly, of its receptor-binding-domain (RBD). Mutations in spike impacting antibody or ACE2 binding are known, but the effect of mutation synergy is less explored. We engineered 22 spike-pseudotyped lentiviruses containing individual and combined mutations, and confirmed that E484K evades antibody neutralization elicited by infection or vaccination, a capacity augmented when complemented by K417N and N501Y mutations. In silico analysis provided an explanation for E484K immune evasion. E484 frequently engages in interactions with antibodies but not with ACE2. Importantly, we identified a novel amino acid of concern, S494, which shares a similar pattern. Using the already circulating mutation S494P, we found that it reduces antibody neutralization of convalescent sera. This amino acid emerges as an additional hotspot for immune evasion and a target for therapies, vaccines and diagnostics.One-Sentence SummaryAmino acids in SARS-CoV-2 spike protein implicated in immune evasion are biased for binding to neutralizing antibodies but dispensable for binding the host receptor angiotensin-converting enzyme 2.


2019 ◽  
Author(s):  
Anezia Kourkoulou ◽  
Pothos Grevias ◽  
George Lambrinidis ◽  
Euan Pyle ◽  
Mariangela Dionysopoulou ◽  
...  

AbstractTransporters are transmembrane proteins that mediate the selective translocation of solutes across biological membranes. Recently, we have shown that specific interactions with plasma membrane phospholipids are essential for formation and/or stability of functional dimers of the purine transporter, UapA, a prototypic eukaryotic member of the ubiquitous NAT family. Here, we show that distinct interactions of UapA with specific or annular lipids are essential for ab initio formation of functional dimers in the ER or ER-exit and further subcellular trafficking. Through genetic screens we identify mutations that restore defects in dimer formation and/or trafficking. Suppressors of defective dimerization restore ab initio formation of UapA dimers in the ER. Most of these suppressors are located in the movable core domain, but also in the core-dimerization interface and in residues of the dimerization domain exposed to lipids. Molecular Dynamics suggest the majority of suppressors stabilize interhelical interactions in the core domain and thus assist the formation of functional UapA dimers. Among suppressors restoring dimerization, a specific mutation, T401P, was also isolated independently as a suppressor restoring trafficking, suggesting that stabilization of the core domain restores function by sustaining structural defects caused by abolishment of essential interactions with specific or annular lipids. Importantly, introduction of mutations topologically equivalent to T401P into a rat homologue of UapA, namely rSNBT1, permitted the functional expression of a mammalian NAT in A. nidulans. Thus, our results provide a potential route for the functional expression and manipulation of mammalian transporters in the model Aspergillus system.Author SummaryTransporters are proteins found in biological membranes, where they are involved in the selective movement of nutrients, ions, drugs and other small molecules across membranes. Consequently, their function is essential for cell viability, while their malfunction often results to disease. Recent findings have suggested that transporter functioning depends on proper interactions with associated membrane lipids. In this article, using UapA, a very well-studied transporter from a model fungus (Aspergillus nidulans), we show that two types of specific interactions with lipids are essential for tight and specific association of two UapA molecules in a single functional unit (UapA dimer), and for targeting to the cell membrane and transport activity. The first type of interaction concerns specific lipids associating with positively charged amino acids at the interface of the UapA dimer, whereas the other type involves lipids that interact with charged amino acids at the outer shell of the transporter. Most interestingly, defects due to abolishment of UapA-lipid interactions were shown to be restored by mutations that increase UapA stability. Using this information, we genetically manipulated and increased the stability of a mammalian transporter (rSNBT1), and thus achieved its functional expression in the experimentally tractable system of A. nidulans.


Sign in / Sign up

Export Citation Format

Share Document