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Journal ArticleDOI

Computational strategies for protein conformational ensemble detection.

01 Feb 2022-Current Opinion in Structural Biology (Elsevier Current Trends)-Vol. 72, pp 79-87
TL;DR: The ability to detect and juggle protein conformations supplemented by a physics-based understanding has implications for not only in vivo problems but also for resistance impeding drug discovery and bionano-sensor design as discussed by the authors.
About: This article is published in Current Opinion in Structural Biology.The article was published on 2022-02-01. It has received 5 citations till now. The article focuses on the topics: Evolvability & Computational biology.
Citations
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Journal ArticleDOI
TL;DR: In this article , the authors focus on the mechanism of protein conformational switching and its regulation by small molecules and emphasize the rational approaches to control protein oligomerization with small molecules that offer exciting opportunities for investigation of novel biological mechanisms and drug discovery.

2 citations

Journal ArticleDOI
TL;DR: It is found that the whole enzyme is synchronized to the motions of the substrate, irrespective of the mutation introducing gain-of-function or loss-of function, and hydrogen bond dynamics recorded on sub-μs time scales provide the necessary fingerprints to decipher the various mechanisms at play.
Abstract: Antibiotic resistance is a global health problem in which mutations occurring in functional proteins render drugs ineffective. The working mechanisms of the arising mutants are seldom apparent; a methodology to decipher these mechanisms systematically would render devising therapies to control the arising mutational pathways possible. Here we utilize Cα–Cβ bond vector relaxations obtained from moderate length MD trajectories to determine conduits for functionality of the resistance conferring mutants of Escherichia coli dihydrofolate reductase. We find that the whole enzyme is synchronized to the motions of the substrate, irrespective of the mutation introducing gain-of-function or loss-of function. The total coordination of the motions suggests changes in the hydrogen bond dynamics with respect to the wild type as a possible route to determine and classify the mode-of-action of individual mutants. As a result, nine trimethoprim-resistant point mutations arising frequently in evolution experiments are categorized. One group of mutants that display the largest occurrence (L28R, W30G) work directly by modifying the dihydrofolate binding region. Conversely, W30R works indirectly by the formation of the E139–R30 salt bridge which releases energy resulting from tight binding by distorting the binding cavity. A third group (D27E, F153S, I94L) arising as single, resistance invoking mutants in evolution experiment trajectories allosterically and dynamically affects a hydrogen bonding motif formed at residues 59–69–71 which in turn modifies the binding site dynamics. The final group (I5F, A26T, R98P) consists of those mutants that have properties most similar to the wild type; these only appear after one of the other mutants is fixed on the protein structure and therefore display clear epistasis. Thus, we show that the binding event is governed by the entire enzyme dynamics while the binding site residues play gating roles. The adjustments made in the total enzyme in response to point mutations are what make quantifying and pinpointing their effect a hard problem. Here, we show that hydrogen bond dynamics recorded on sub-μs time scales provide the necessary fingerprints to decipher the various mechanisms at play.

1 citations

Journal ArticleDOI
TL;DR: In this paper , the authors examine the state of knowledge at the intersection of enzyme engineering and protein dynamics, describe current challenges and highlight pioneering work in the nascent area of dynamic engineering.
Abstract: Enzyme engineering has become a widely adopted practice in research labs and industry. In parallel, the past decades have seen tremendous strides in characterizing the dynamics of proteins, using a growing array of methodologies. Importantly, links have been established between the dynamics of proteins and their function. Characterizing the dynamics of an enzyme prior to, and following, its engineering is beginning to inform on the potential of 'dynamic engineering', i.e., the rational modification of protein dynamics to alter enzyme function. Here we examine the state of knowledge at the intersection of enzyme engineering and protein dynamics, describe current challenges and highlight pioneering work in the nascent area of dynamic engineering.

1 citations

Journal ArticleDOI
TL;DR: In this article , the authors combine molecular dynamics simulations with small angle x-ray scattering (SAXS) measurements to investigate the range of conformations that can be adopted by a pH/ionic strength sensitive protein and to quantify its distinct populations in solution.
Abstract: This study combines molecular dynamics (MD) simulations with small angle x-ray scattering (SAXS) measurements to investigate the range of conformations that can be adopted by a pH/ionic strength (IS) sensitive protein and to quantify its distinct populations in solution. To explore how the conformational distribution of proteins may be modified in the environmental niches of biological media, we focus on the periplasmic ferric binding protein A (FbpA) from Haemophilus influenzae involved in the mechanism by which bacteria capture iron from higher organisms. We examine iron-binding/release mechanisms of FbpA in varying conditions simulating its biological environment. While we show that these changes fall within the detectable range for SAXS as evidenced by differences observed in the theoretical scattering patterns calculated from the crystal structure models of apo and holo forms, detection of conformational changes due to the point mutation D52A and changes in ionic strength (IS) from SAXS scattering profiles have been challenging. Here, to reach conclusions, statistical analyses with SAXS profiles and results from different techniques were combined in a complementary fashion. The SAXS data complemented by size exclusion chromatography point to multiple and/or alternative conformations at physiological IS, whereas they are well-explained by single crystallographic structures in low IS buffers. By fitting the SAXS data with unique conformations sampled by a series of MD simulations under conditions mimicking the buffers, we quantify the populations of the occupied substates. We also find that the D52A mutant that we predicted by coarse-grained computational modeling to allosterically control the iron binding site in FbpA, responds to the environmental changes in our experiments with conformational selection scenarios that differ from those of the wild type.
Journal ArticleDOI
TL;DR: Wu et al. as discussed by the authors studied and discussed the systematic methods applied by the smart park system in the renovation and renewal of urban parks, to discuss the common problems and solutions faced in urban parks today.
Abstract: Nowadays, in the context of smart city construction, the changes brought by the smart system to the city are not only material intelligence, but also because the smart system is completed by the cooperation of human wisdom and the wisdom of things, it is even more enhanced. There are various connections between people and people and cities. In this paper, the construction of urban parks, its management, and service requirements also show a trend of diversified development. However, some traditional urban parks cannot meet the new social needs. The application of smart park systems in their renovation is an important way for urban parks to rejuvenate and is an indispensable part of smart city construction. For urban parks, the upgrade of smartization in the traditional park model is not only an inevitable trend in the development of information technology but also an important direction for the future construction of parks. The purpose of this paper is to study and discuss the systematic methods applied by the smart park system in the renovation and renewal of urban parks, to discuss the common problems and solutions faced in the renovation and renewal of urban parks today, and to realize the renovation of the smart park system of urban parks. And by studying the application background, ways, and needs of the smart park system, it will carry out practical exploration on the renovation and renewal of Wuhan Jiefang Park. Through the analysis of the current situation of the Jiefang Park and the interpretation of the existing problems, special transformation is carried out under the guidance of the smart park system according to the existing problems, and the methods and systems of the application of the smart park system are summarized through practice. From a practical point of view, the update design strategy proposed in this paper is tested.
References
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Journal ArticleDOI
TL;DR: A new tool is presented and applied to the retinol-binding protein, which indicates enhanced flexibility in the region of entry to the ligand binding site and for the portion of the protein binding to its carrier protein.

1,573 citations

Journal ArticleDOI
TL;DR: A normal mode analysis of 20 proteins in 'open' or 'closed' forms was performed using simple potential and protein models, the quality of the results was found to depend upon the form of the protein studied, normal modes obtained with the open form of a given protein comparing better with the conformational change than those obtaining with the closed form.
Abstract: A normal mode analysis of 20 proteins in 'open' or 'closed' forms was performed using simple potential and protein models. The quality of the results was found to depend upon the form of the protein studied, normal modes obtained with the open form of a given protein comparing better with the conformational change than those obtained with the closed form. Moreover, when the motion of the protein is a highly collective one, then, in all cases considered, there is a single low-frequency normal mode whose direction compares well with the conformational change. When it is not, in most cases there is still a single low-frequency normal mode giving a good description of the pattern of the atomic displacements, as they are observed experimentally during the conformational change. Hence a lot of information on the nature of the conformational change of a protein is often found in a single low-frequency normal mode of its open form. Since this information can be obtained through the normal mode analysis of a model as simple as that used in the present study, it is likely that the property captured by such an analysis is for the most part a property of the shape of the protein itself. One of the points that has to be clarified now is whether or not amino acid sequences have been selected in order to allow proteins to follow a single normal mode direction, as least at the very beginning of their conformational change.

878 citations

Journal ArticleDOI
TL;DR: Geometrical considerations are used to provide a different perspective on the fact that a few selected amino acids act as nucleation centers for protein folding and show that they have the "small-world" feature of having a limited set of vertices with large connectivity.
Abstract: We use geometrical considerations to provide a different perspective on the fact that a few selected amino acids, the so-called "key residues," act as nucleation centers for protein folding. By constructing graphs corresponding to protein structures we show that they have the "small-world" feature of having a limited set of vertices with large connectivity. These vertices correspond to the key residues that play the role of "hubs" in the network of interactions that stabilize the structure of the transition state.

385 citations

Journal ArticleDOI
TL;DR: The coarse-grained Martini force field is widely used in biomolecular simulations as discussed by the authors, which allows accurate predictions of molecular packing and interactions in general, exemplified with a vast and diverse set of applications, ranging from oil/water partitioning and miscibility data to complex molecular systems, involving protein-protein and protein-lipid interactions and material science applications as ionic liquids and aedamers.
Abstract: The coarse-grained Martini force field is widely used in biomolecular simulations. Here we present the refined model, Martini 3 ( http://cgmartini.nl ), with an improved interaction balance, new bead types and expanded ability to include specific interactions representing, for example, hydrogen bonding and electronic polarizability. The updated model allows more accurate predictions of molecular packing and interactions in general, which is exemplified with a vast and diverse set of applications, ranging from oil/water partitioning and miscibility data to complex molecular systems, involving protein-protein and protein-lipid interactions and material science applications as ionic liquids and aedamers.

346 citations

Journal ArticleDOI
TL;DR: In this article, the authors show that residues in folded proteins are distributed according to a "small-world" topology, and that the core residues have the same local packing arrangements irrespective of protein size.

339 citations