Understanding the importance of the aromatic amino-acid residues as hot-spots

Moreira, Irina S.; Martins, João M.; Ramos, Rui Miguel; Fernandes, Pedro A.; Ramos, Maria João

doi:10.1016/j.bbapap.2012.07.005

Cited by 43 publications

(43 citation statements)

References 64 publications

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“…16,26,27 Many other authors have focused their attention in this subject, either by proposing modifications to the original one (Liang et al 28 ) or complementing it. [29][30][31][32] In this work we subjected several proteinprotein (PP) and protein-DNA (PDNA) complexes to Molecular Dynamics (MD) simulations in explicit and implicit solvent. Several SASA features were measured and their use as hot-spot differentiators was statistically evaluated.…”

Section: Introductionmentioning

confidence: 99%

Solvent‐accessible surface area: How well can be applied to hot‐spot detection?

et al. 2013

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A detailed comprehension of protein-based interfaces is essential for the rational drug development. One of the key features of these interfaces is their solvent accessible surface area profile. With that in mind, we tested a group of 12 SASA-based features for their ability to correlate and differentiate hot- and null-spots. These were tested in three different data sets, explicit water MD, implicit water MD, and static PDB structure. We found no discernible improvement with the use of more comprehensive data sets obtained from molecular dynamics. The features tested were shown to be capable of discerning between hot- and null-spots, while presenting low correlations. Residue standardization such as rel SASAi or rel/res SASAi , improved the features as a tool to predict ΔΔGbinding values. A new method using support machine learning algorithms was developed: SBHD (Sasa-Based Hot-spot Detection). This method presents a precision, recall, and F1 score of 0.72, 0.81, and 0.76 for the training set and 0.91, 0.73, and 0.81 for an independent test set.

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Section: Introductionmentioning

confidence: 99%

Solvent‐accessible surface area: How well can be applied to hot‐spot detection?

et al. 2013

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“…However, in our study, we obtained an high energetic contribution to Leu54, Leu117, and Leu121 from REN; Leu10 and Leu56 from ANG; Phe253 and Phe286 from REN; Phe8 and Phe67 from ANG; Val11 at ANG; Met16 and Met120 from REN; Lys293 and Lys 55 from REN and ANG; Gln318 and Glu15 from ANG. Similarly to the current REN:ANG complex, there are other protein-protein systems (e.g., MDM2:p53, ZipA:FtsZ, and VEGF:Flt-1 complexes) (46,47) in which hydrophobic and aromatic residues, such as Leu and Phe, were identified as hot spots due to their great energetic contributions to the establishment of strong hydrophobic and cation-p interactions within the interfacial region. Table 4 summarizes the energetic contribution of all the individual residues to the differences in the binding free energies (DDG binding ) between wild-type REN:ANG and alanine mutant variants for hot, warm, and null spots identified.…”

Section: Resultsmentioning

confidence: 88%

“…SASA REN or SASA ANG of 101.21 AE 2.71 A 2 that decreases to46.60 AE 2.70 A 2 upon complexation (SASA lost of 54.61 AE 0.08 A 2 ). Null spots interact preferentially within their own protein, having small values of SASA REN or SASA ANG (average of 60.60 AE 1.36 A 2 ) that slightly decreases to 40.39 AE 1.30 A 2 within the complex, and they present a little SASA lost of 20.21 AE 0.06 A 2 .…”

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confidence: 99%

Discovery of New Sites for Drug Binding to the Hypertension‐Related Renin–Angiotensinogen Complex

2014

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Renin (REN) is a key drug target to stop the hypertension cascade, but thus far only one direct inhibitor has been made commercially available. In this study, we assess an innovative REN inhibition strategy, by targeting the interface of the renin:angiotensinogen (REN:ANG) complex. We characterized the energetic role of interfacial residues of REN:ANG and identified the ones responsible for protein:protein binding, which can serve as drug targets for disruption of the REN:ANG association. For this purpose, we applied a computational alanine scanning mutagenesis protocol, which measures the contribution of each side chain for the protein:protein binding free energy with an accuracy of ≈ 1 kcal/mol. As a result, in REN and ANG, six and eight residues were found to be critical for binding, respectively. The leading force behind REN:ANG complexation was found to be the hydrophobic effect. The binding free energy per residue was found to be proportional to the buried area. Residues responsible for binding were occluded from water at the complex, which promotes an efficient pairing between the two proteins. Two druggable pockets involving critical residues for binding were found on the surface of REN, where small druglike molecules can bind and disrupt the ANG:REN association that may provide an efficient way to achieve REN inhibition and control hypertension.

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“…Noteworthy, short helices yield access of Phe, Tyr, Val, and Trp in all type of proteins. Presence of three aromatic residues (F, Y, and W) in the short helices points to their potential role in the protein–protein and protein–nucleic acid recognition and interactions, and involvement into the protein function . Preliminary inspection of the secondary structure annotation in PDB was suggestive of considering two sets of α‐helices with the sizes 5–40 and 5–70 amino acids, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Presence of three aromatic residues (F, Y, and W) in the short helices points to their potential role in the protein-protein and proteinnucleic acid recognition and interactions, and involvement into the protein function. [49][50][51] Preliminary Figure 1. The Z-score predictor of protein a-helicity.…”

Section: Resultsmentioning

confidence: 99%

Organization of the multiaminoacyl‐tRNA synthetase complex and the cotranslational protein folding

et al. 2015

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Aminoacyl-tRNA synthetases (ARSs) play an essential role in the protein synthesis by catalyzing an attachment of their cognate amino acids to tRNAs. Unlike their prokaryotic counterparts, ARSs in higher eukaryotes form a multiaminoacyl-tRNA synthetase complex (MARS), consisting of the subset of ARS polypeptides and three auxiliary proteins. The intriguing feature of MARS complex is the presence of only nine out of twenty ARSs, specific for Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met, and Pro, regardless of the organism, cell, or tissue types. Although existence of MARSs complex in higher eukaryotes has been already known for more than four decades, its functional significance remains elusive. We found that seven of the nine corresponding amino acids (Arg, Gln, Glu, Ile, Leu, Lys, and Met) together with Ala form a predictor of the protein a-helicity. Remarkably, all amino acids (besides Ala) in the predictor have the highest possible number of side-chain rotamers. Therefore, compositional bias of a typical ahelix can contribute to the helix's stability by increasing the entropy of the folded state. It also appears that position-specific a-helical propensity, specifically periodic alternation of charged and hydrophobic residues in the helices, may well be provided by the structural organization of the complex. Considering characteristics of MARS complex from the perspective of the a-helicity, we hypothesize that specific composition and structure of the complex represents a functional mechanism for coordination of translation with the fast and correct folding of amphiphilic a-helices.

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Understanding the importance of the aromatic amino-acid residues as hot-spots

Cited by 43 publications

References 64 publications

Solvent‐accessible surface area: How well can be applied to hot‐spot detection?

Solvent‐accessible surface area: How well can be applied to hot‐spot detection?

Discovery of New Sites for Drug Binding to the Hypertension‐Related Renin–Angiotensinogen Complex

Organization of the multiaminoacyl‐tRNA synthetase complex and the cotranslational protein folding

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