Prediction of impacts of mutations on protein structure and interactions: SDM, a statistical approach, and mCSM, using machine learning

Pandurangan, Arun Prasad; Blundell, Tom L.

doi:10.1002/pro.3774

Cited by 68 publications

(42 citation statements)

References 126 publications

(194 reference statements)

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“…A predicted tertiary structure PDB file was used as input in SDM online tool to predict variant effect on stability and relative solvent accessibility 56 . SDM was used to predict stability as it is the least biased pipeline 57 . 3D visualization was obtained using chimera 1.13.1 software package 58 .…”

Section: Methodsmentioning

confidence: 99%

Novel Variations in Native Ethiopian Goat breeds PRNP Gene and Their Potential Effect on Prion Protein Stability

Teferedegn

Yaman

Ün

2020

Sci Rep

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Scrapie is a lethal neurodegenerative disease of sheep and goats caused by the misfolding of the prion protein. Variants such as M142, D145, S146, H154, Q211, and K222 were experimentally found to increase resistance or extend scrapie incubation period in goats. We aimed to identify polymorphisms in the Afar and Arsi-Bale goat breeds of Ethiopia and computationally assess the effect of variants on prion protein stability. In the present study, four non-synonymous novel polymorphisms G67S, W68R, G69D, and R159H in the first octapeptide repeat and the highly conserved C-terminus globular domain of goat PrP were detected. The resistant genotype, S146, was detected in >50% of the present population. The current study population showed a genetic diversity in Ethiopian goat breeds. In the insilico analysis, the R68 variant was predicted to increase stability while S67, D69, and H159 decrease the stability of prion protein. The new variants in the octapeptide repeat motif were predicted to decrease amyloidogenicity but H159 increased the hotspot sequence amyloidogenic propensity. These novel variants could be the source of conformational flexibility that may trigger the gain or loss of function by prion protein. Further experimental study is required to depict the actual effects of variants on prion protein stability. Prion diseases are lethal neurodegenerative disease of humans and animals caused by the misfolding of prion protein 1. Despite being rare, the diseases are lethal and have resulted in huge animal loss over a course of time in several countries 2. The oldest prion disease is scrapie that affects small ruminants 3,4. Though the exact pathomechanism is not yet known, predisposing genetic variants have been documented in different species 5. A wide range of polymorphisms have been identified in goats either as protective or susceptible alleles. A recent review reported the presence of more than 50 polymorphisms in goat prion protein-coding gene (PRNP) 6. Among the variants, G127S, M142I, H143R, N146S, R154H, Q222K, and S240P are the most common substitutions worldwide 7,8. Similarly, R139S in Algeria 9 , A116V in Tanzania 10 , G134E and Q163P in Turkey 11 and G127A and T193I in Ethiopia 12 were novel (at the time of the report) substitutions discovered in the respective area of study. Alleles such as M142, D145, S146, H154, Q211, and K222 were experimentally found to either extend scrapie incubation period or increase resistance 8,13-16. Experimental studies reported the link between sequence variation in the functional domains of prion protein and scrapie disease development 17,18. Substitutions in the palindrome and glycine-rich motifs were identified to affect amyloid fibril formation 19. Although the C terminal globular domain is often involved in the PrP c to PrP Sc conversion process, octapeptide repeat regions are also known to influence the structural dynamics of prion protein. Insertion or deletion of octapeptide repeat for example, induce disease phenotypes 20. According to the FAOSTAT 2017 report, 3...

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Section: Methodsmentioning

confidence: 99%

Novel Variations in Native Ethiopian Goat breeds PRNP Gene and Their Potential Effect on Prion Protein Stability

Teferedegn

Yaman

Ün

2020

Sci Rep

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“…Therefore, besides the gene expression and complementation experiments to understand the VISA molecular mechanisms, the importance of knowledge about protein structure mapping of mutations and predicting of the impact of the mutation on the disruption of protein function using molecular computational approaches can provide new insight into the mechanisms underlying VISA development and help to design novel therapeutic strategies 18 .…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Molecular Insight Into the Mutation Within Critical Zinc2+-Binding Site in the PAS Domain of WalK in Vancomycin-Intermediate Resistant Staphylococcus Aureus

Baseri

Peerayeh

Bakhshi

2020

Preprint

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Vancomycin-intermediate resistant Staphylococcus aureus (VISA), one of the common causes of nosocomial infection, is developed by mutations, including in walKR, with unclear molecular mechanisms. Although studies have verified some of these mutations, there are a few studies to pay attention to the importance of molecular modeling of mutations. Here, the Sanger sequencing for comparing gene sequences of WlKR between a VISA and its parental strain revealed mutation WalK-H364R. Structural protein mapping showed that H364R was located in a functional zinc ion coordinating residue within the cytoplasmic Per-Arnt-Sim (PAS) domain. The structural and functional effects of this mutation were analyzed using molecular computational approaches based on the recently determined crystal structures of the PAS domain of S. aureus. WalK-H364R was predicted to destabilize protein and decrease WalK interactions with proteins and nucleic acids. The qRT-PCR method showed downregulation of walKR and WalKR-regulated autolysins, which verified the molecular computational results.Overall, WalK-H364R within a critical metal-coordinating site is linked to VISA development through the walKR gene expression changes as well as the destructive effects on protein.Therefore, molecular modeling can be provided detailed insight into the molecular mechanism of VISA development, in particular, where complementation experiments are not readily available.

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“…These proteins were selected owing to their curial role in host-viral interactome. Structural effects of SARS-CoV-2 mutations were studied using variant analysis module of COVID-3D suite [9, 10]. Images were created using PyMol [11].…”

Section: Figurementioning

confidence: 99%

Structure-function investigation of a new VUI-202012/01 SARS-CoV-2 variant

Singh

Rahman³

et al. 2021

Preprint

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The SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus) has accumulated multiple mutations during its global circulation. Recently, a new strain of SARS-CoV-2 (VUI 202012/01) had been identified leading to sudden spike in COVID-19 cases in South-East England. The strain has accumulated 23 mutations which have been linked to its immune evasion and higher transmission capabilities. Here, we have highlighted structural-function impact of crucial mutations occurring in spike (S), ORF8 and nucleocapsid (N) protein of SARS-CoV-2. Some of these mutations might confer higher fitness to SARS-CoV-2.SummarySince initial outbreak of COVID-19 in Wuhan city of central China, its causative agent; SARS-CoV-2 virus has claimed more than 1.7 million lives out of 77 million populations and still counting. As a result of global research efforts involving public-private-partnerships, more than 0.2 million complete genome sequences have been made available through Global Initiative on Sharing All Influenza Data (GISAID). Similar to previously characterized coronaviruses (CoVs), the positive-sense single-stranded RNA SARS-CoV-2 genome codes for ORF1ab non-structural proteins (nsp(s)) followed by ten or more structural/nsps [1, 2]. The structural proteins include crucial spike (S), nucleocapsid (N), membrane (M), and envelope (E) proteins. The S protein mediates initial contacts with human hosts while the E and M proteins function in viral assembly and budding. In recent reports on evolution of SARS-CoV-2, three lineage defining non-synonymous mutations; namely D614G in S protein (Clade G), G251V in ORF3a (Clade V) and L84S in ORF 8 (Clade S) were observed [2–4]. The latest pioneering works by Plante et al and Hou et al have shown that compared to ancestral strain, the ubiquitous D614G variant (clade G) of SARS-CoV-2 exhibits efficient replication in upper respiratory tract epithelial cells and transmission, thereby conferring higher fitness [5, 6]. As per latest WHO reports on COVID-19, a new strain referred as SARS-CoV-2 VUI 202012/01 (Variant Under Investigation, year 2020, month 12, variant 01) had been identified as a part of virological and epidemiological analysis, due to sudden rise in COVID-19 detected cases in South-East England [7]. Preliminary reports from UK suggested higher transmissibility (increase by 40-70%) of this strain, escalating Ro (basic reproduction number) of virus to 1.5-1.7 [7, 8]. This apparent fast spreading variant inculcates 23 mutations; 13 non-synonymous, 6 synonymous and 4 amino acid deletions [7]. In the current scenario, where immunization programs have already commenced in nations highly affected by COVID-19, advent of this new strain variant has raised concerns worldwide on its possible role in disease severity and antibody responses. The mutations also could also have significant impact on diagnostic assays owing to S gene target failures.

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Prediction of impacts of mutations on protein structure and interactions: SDM, a statistical approach, and mCSM, using machine learning

Cited by 68 publications

References 126 publications

Novel Variations in Native Ethiopian Goat breeds PRNP Gene and Their Potential Effect on Prion Protein Stability

Novel Variations in Native Ethiopian Goat breeds PRNP Gene and Their Potential Effect on Prion Protein Stability

WITHDRAWN: Molecular Insight Into the Mutation Within Critical Zinc2+-Binding Site in the PAS Domain of WalK in Vancomycin-Intermediate Resistant Staphylococcus Aureus

Structure-function investigation of a new VUI-202012/01 SARS-CoV-2 variant

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