{"title":"IGPRED: Combination of convolutional neural and graph convolutional networks for protein secondary structure prediction","authors":"Yasin Görmez","doi":"10.1002/prot.26354","DOIUrl":"https://doi.org/10.1002/prot.26354","url":null,"abstract":"","PeriodicalId":20789,"journal":{"name":"Proteins: Structure","volume":"59 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80871315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human transthyretin (TTR) is a homotetrameric plasma protein associated with a high percentage of β‐sheet, which forms amyloid fibrils and accumulates in tissues or extracellular matrix to cause amyloid diseases. Free energy simulations based on all‐atom molecular dynamics simulations were carried out to analyze the effects of the His88 → Arg, Phe, and Tyr mutations on the stability of human TTR. The calculated free energy change differences (ΔΔG) caused by the His → Arg, Phe, and Tyr mutations at position 88 are 6.48 ± 0.45, −9.99 ± 0.54, and 2.66 ± 0.33 kcal/mol, respectively. These calculated free energy change differences between wild type and the mutants are in excellent agreement with prior experimental values. Our simulation results show that the wild type of the TTR is more stable than H88R and H88Y mutants, whereas it is less stable than the H88F mutant. The free energy component analysis shows that the primary contribution to the free energy change difference (ΔΔG) for the His → Arg mutation arises from electrostatic interaction; the ΔΔG for the His → Phe mutation is from van der Waals and electrostatic interactions and that for the His → Tyr mutation from covalent interaction. The simulation results show that the free energy calculation with thermodynamic integration is beneficial for understanding the detailed microscopic mechanism of protein stability. The implications of the results for understanding stabilizing and destabilizing effect of the mutation and the contribution to protein stability are discussed.
{"title":"Modulation of human transthyretin stability by the mutations at histidine 88 studied by free energy simulation","authors":"Kyung-Hoon Lee, K. Kuczera","doi":"10.1002/prot.26353","DOIUrl":"https://doi.org/10.1002/prot.26353","url":null,"abstract":"Human transthyretin (TTR) is a homotetrameric plasma protein associated with a high percentage of β‐sheet, which forms amyloid fibrils and accumulates in tissues or extracellular matrix to cause amyloid diseases. Free energy simulations based on all‐atom molecular dynamics simulations were carried out to analyze the effects of the His88 → Arg, Phe, and Tyr mutations on the stability of human TTR. The calculated free energy change differences (ΔΔG) caused by the His → Arg, Phe, and Tyr mutations at position 88 are 6.48 ± 0.45, −9.99 ± 0.54, and 2.66 ± 0.33 kcal/mol, respectively. These calculated free energy change differences between wild type and the mutants are in excellent agreement with prior experimental values. Our simulation results show that the wild type of the TTR is more stable than H88R and H88Y mutants, whereas it is less stable than the H88F mutant. The free energy component analysis shows that the primary contribution to the free energy change difference (ΔΔG) for the His → Arg mutation arises from electrostatic interaction; the ΔΔG for the His → Phe mutation is from van der Waals and electrostatic interactions and that for the His → Tyr mutation from covalent interaction. The simulation results show that the free energy calculation with thermodynamic integration is beneficial for understanding the detailed microscopic mechanism of protein stability. The implications of the results for understanding stabilizing and destabilizing effect of the mutation and the contribution to protein stability are discussed.","PeriodicalId":20789,"journal":{"name":"Proteins: Structure","volume":"47 1","pages":"1825 - 1836"},"PeriodicalIF":0.0,"publicationDate":"2022-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91155761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Olagunju, Jennifer Loschwitz, O. Olubiyi, B. Strodel
Sickle cell disease is a hemoglobinopathy resulting from a point mutation from glutamate to valine at position six of the β‐globin chains of hemoglobin. This mutation gives rise to pathological aggregation of the sickle hemoglobin and, as a result, impaired oxygen binding, misshapen and short‐lived erythrocytes, and anemia. We aim to understand the structural effects caused by the single Glu6Val mutation leading to protein aggregation. To this end, we perform multiscale molecular dynamics simulations employing atomistic and coarse‐grained models of both wild‐type and sickle hemoglobin. We analyze the dynamics of hemoglobin monomers and dimers, study the aggregation of wild‐type and sickle hemoglobin into decamers, and analyze the protein–protein interactions in the resulting aggregates. We find that the aggregation of sickle hemoglobin is driven by both hydrophobic and electrostatic protein–protein interactions involving the mutation site and surrounding residues, leading to an extended interaction area and thus stable aggregates. The wild‐type protein can also self‐assemble, which, however, results from isolated interprotein salt bridges that do not yield stable aggregates. This knowledge can be exploited for the development of sickle hemoglobin‐aggregation inhibitors.
{"title":"Multiscale MD simulations of wild‐type and sickle hemoglobin aggregation","authors":"M. Olagunju, Jennifer Loschwitz, O. Olubiyi, B. Strodel","doi":"10.1002/prot.26352","DOIUrl":"https://doi.org/10.1002/prot.26352","url":null,"abstract":"Sickle cell disease is a hemoglobinopathy resulting from a point mutation from glutamate to valine at position six of the β‐globin chains of hemoglobin. This mutation gives rise to pathological aggregation of the sickle hemoglobin and, as a result, impaired oxygen binding, misshapen and short‐lived erythrocytes, and anemia. We aim to understand the structural effects caused by the single Glu6Val mutation leading to protein aggregation. To this end, we perform multiscale molecular dynamics simulations employing atomistic and coarse‐grained models of both wild‐type and sickle hemoglobin. We analyze the dynamics of hemoglobin monomers and dimers, study the aggregation of wild‐type and sickle hemoglobin into decamers, and analyze the protein–protein interactions in the resulting aggregates. We find that the aggregation of sickle hemoglobin is driven by both hydrophobic and electrostatic protein–protein interactions involving the mutation site and surrounding residues, leading to an extended interaction area and thus stable aggregates. The wild‐type protein can also self‐assemble, which, however, results from isolated interprotein salt bridges that do not yield stable aggregates. This knowledge can be exploited for the development of sickle hemoglobin‐aggregation inhibitors.","PeriodicalId":20789,"journal":{"name":"Proteins: Structure","volume":"31 1","pages":"1811 - 1824"},"PeriodicalIF":0.0,"publicationDate":"2022-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85256083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yerli Marín-Tovar, H. Serrano-Posada, A. Díaz-Vilchis, E. Rudiño-Piñera
Proliferating cell nuclear antigen (PCNA) is an essential protein for cell viability in archaea and eukarya, since it is involved in DNA replication and repair. In order to obtain insights regarding the characteristics that confer radioresistance, the structural study of the PCNA from Thermococcus gammatolerans (PCNATg) in a gradient of ionizing radiation by X‐ray crystallography was carried out, together with a bioinformatic analysis of homotrimeric PCNA structures, their sequences, and their molecular interactions. The results obtained from the datasets and the accumulated radiation dose for the last collection from three crystals revealed moderate and localized damage, since even with the loss of resolution, the electron density map corresponding to the last collection allowed to build the whole structure. Attempting to understand this behavior, multiple sequence alignments, and structural superpositions were performed, revealing that PCNA is a protein with a poorly conserved sequence, but with a highly conserved structure. The PCNATg presented the highest percentage of charged residues, mostly negatively charged, with a proportion of glutamate more than double aspartate, lack of cysteines and tryptophan, besides a high number of salt bridges. The structural study by X‐ray crystallography reveals that the PCNATg has the intrinsic ability to resist high levels of ionizing radiation, and the bioinformatic analysis suggests that molecular evolution selected a particular composition of amino acid residues, and their consequent network of synergistic interactions for extreme conditions, as a collateral effect, conferring radioresistance to a protein involved in the chromosomal DNA metabolism of a radioresistant microorganism.
{"title":"PCNA from Thermococcus gammatolerans: A protein involved in chromosomal DNA metabolism intrinsically resistant at high levels of ionizing radiation","authors":"Yerli Marín-Tovar, H. Serrano-Posada, A. Díaz-Vilchis, E. Rudiño-Piñera","doi":"10.1002/prot.26346","DOIUrl":"https://doi.org/10.1002/prot.26346","url":null,"abstract":"Proliferating cell nuclear antigen (PCNA) is an essential protein for cell viability in archaea and eukarya, since it is involved in DNA replication and repair. In order to obtain insights regarding the characteristics that confer radioresistance, the structural study of the PCNA from Thermococcus gammatolerans (PCNATg) in a gradient of ionizing radiation by X‐ray crystallography was carried out, together with a bioinformatic analysis of homotrimeric PCNA structures, their sequences, and their molecular interactions. The results obtained from the datasets and the accumulated radiation dose for the last collection from three crystals revealed moderate and localized damage, since even with the loss of resolution, the electron density map corresponding to the last collection allowed to build the whole structure. Attempting to understand this behavior, multiple sequence alignments, and structural superpositions were performed, revealing that PCNA is a protein with a poorly conserved sequence, but with a highly conserved structure. The PCNATg presented the highest percentage of charged residues, mostly negatively charged, with a proportion of glutamate more than double aspartate, lack of cysteines and tryptophan, besides a high number of salt bridges. The structural study by X‐ray crystallography reveals that the PCNATg has the intrinsic ability to resist high levels of ionizing radiation, and the bioinformatic analysis suggests that molecular evolution selected a particular composition of amino acid residues, and their consequent network of synergistic interactions for extreme conditions, as a collateral effect, conferring radioresistance to a protein involved in the chromosomal DNA metabolism of a radioresistant microorganism.","PeriodicalId":20789,"journal":{"name":"Proteins: Structure","volume":"55 1","pages":"1684 - 1698"},"PeriodicalIF":0.0,"publicationDate":"2022-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86678787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Issue Information ‐ Forthcoming","authors":"K. T. Rahn, Robert S. Phillips","doi":"10.1002/prot.26111","DOIUrl":"https://doi.org/10.1002/prot.26111","url":null,"abstract":"","PeriodicalId":20789,"journal":{"name":"Proteins: Structure","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73266082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Issue Information ‐ Table of Content","authors":"","doi":"10.1002/prot.26110","DOIUrl":"https://doi.org/10.1002/prot.26110","url":null,"abstract":"","PeriodicalId":20789,"journal":{"name":"Proteins: Structure","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80453315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Issue Information ‐ Table of Content","authors":"","doi":"10.1002/prot.26106","DOIUrl":"https://doi.org/10.1002/prot.26106","url":null,"abstract":"","PeriodicalId":20789,"journal":{"name":"Proteins: Structure","volume":"92 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85547535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The startling diversity in αβ T‐cell receptor (TCR) sequences and structures complicates molecular‐level analyses of the specificity and sensitivity determining T‐cell immunogenicity. A number of three‐dimensional (3D) structures are now available of ternary complexes between TCRs and peptides: major histocompatibility complexes (pMHC). Here, to glean molecular‐level insights we analyze structures of TCRs bound to human class I nonamer peptide–MHC complexes. Residues at peptide positions 4–8 are found to be particularly important for TCR binding. About 90% of the TCRs hydrogen bond with one or both of the peptide residues at positions 4 and 8 presented by MHC allele HLA‐A2, and this number is still ~79% for peptides presented by other MHC alleles. Residue 8, which lies outside the previously‐identified central peptide region, is crucial for TCR recognition of class I MHC‐presented nonamer peptides. The statistics of the interactions also sheds light on the MHC residues important for TCR binding. The present analysis will aid in the structural modeling of TCR:pMHC complexes and has implications for the rational design of peptide‐based vaccines and T‐cell‐based immunotherapies.
{"title":"Structural patterns in class 1 major histocompatibility complex‐restricted nonamer peptide binding to T‐cell receptors","authors":"R. T, Jeremy C. Smith","doi":"10.1002/prot.26343","DOIUrl":"https://doi.org/10.1002/prot.26343","url":null,"abstract":"The startling diversity in αβ T‐cell receptor (TCR) sequences and structures complicates molecular‐level analyses of the specificity and sensitivity determining T‐cell immunogenicity. A number of three‐dimensional (3D) structures are now available of ternary complexes between TCRs and peptides: major histocompatibility complexes (pMHC). Here, to glean molecular‐level insights we analyze structures of TCRs bound to human class I nonamer peptide–MHC complexes. Residues at peptide positions 4–8 are found to be particularly important for TCR binding. About 90% of the TCRs hydrogen bond with one or both of the peptide residues at positions 4 and 8 presented by MHC allele HLA‐A2, and this number is still ~79% for peptides presented by other MHC alleles. Residue 8, which lies outside the previously‐identified central peptide region, is crucial for TCR recognition of class I MHC‐presented nonamer peptides. The statistics of the interactions also sheds light on the MHC residues important for TCR binding. The present analysis will aid in the structural modeling of TCR:pMHC complexes and has implications for the rational design of peptide‐based vaccines and T‐cell‐based immunotherapies.","PeriodicalId":20789,"journal":{"name":"Proteins: Structure","volume":"122 1","pages":"1645 - 1654"},"PeriodicalIF":0.0,"publicationDate":"2022-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76010377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wanlei Wei, Christopher R. Corbeil, Francis Gaudreault, Christophe Deprez, E. Purisima, T. Sulea
Antibody‐based therapeutics for treatment of various tumors have grown rapidly in recent years. Unfortunately, safety issues, attributed to off‐tumor effects and cytotoxicity, are still a significant concern with the standard of care. Improvements to ensure targeted delivery of antitumor pharmaceuticals are desperately needed. We previously demonstrated that incorporating histidyl pH‐switches in an anti‐HER2 antibody induced selective antigen binding under acidic pH conditions (MAbs 2020;12:1682866). This led to an improved safety profile due to preferential targeting of the oncoprotein in the acidic solid tumor microenvironment. Following this success, we expanded this approach to a set of over 400 antibody structures complexed with over 100 different human oncoproteins, associated with solid tumors. Calculations suggested that mutations to His of certain residue types, namely Trp, Arg, and Tyr, could be significantly more successful for inducing pH‐dependent binding under acidic conditions. Furthermore, 10 positions within the complementarity‐determining region were also predicted to exhibit greater successes. Combined, these two accessible metrics could serve as the basis for a sequence‐based engineering of pH‐selective binding. This approach could be applied to most anticancer antibodies, which lack detailed structural characterization.
{"title":"Antibody mutations favoring pH‐dependent binding in solid tumor microenvironments: Insights from large‐scale structure‐based calculations","authors":"Wanlei Wei, Christopher R. Corbeil, Francis Gaudreault, Christophe Deprez, E. Purisima, T. Sulea","doi":"10.1002/prot.26340","DOIUrl":"https://doi.org/10.1002/prot.26340","url":null,"abstract":"Antibody‐based therapeutics for treatment of various tumors have grown rapidly in recent years. Unfortunately, safety issues, attributed to off‐tumor effects and cytotoxicity, are still a significant concern with the standard of care. Improvements to ensure targeted delivery of antitumor pharmaceuticals are desperately needed. We previously demonstrated that incorporating histidyl pH‐switches in an anti‐HER2 antibody induced selective antigen binding under acidic pH conditions (MAbs 2020;12:1682866). This led to an improved safety profile due to preferential targeting of the oncoprotein in the acidic solid tumor microenvironment. Following this success, we expanded this approach to a set of over 400 antibody structures complexed with over 100 different human oncoproteins, associated with solid tumors. Calculations suggested that mutations to His of certain residue types, namely Trp, Arg, and Tyr, could be significantly more successful for inducing pH‐dependent binding under acidic conditions. Furthermore, 10 positions within the complementarity‐determining region were also predicted to exhibit greater successes. Combined, these two accessible metrics could serve as the basis for a sequence‐based engineering of pH‐selective binding. This approach could be applied to most anticancer antibodies, which lack detailed structural characterization.","PeriodicalId":20789,"journal":{"name":"Proteins: Structure","volume":"107 1","pages":"1538 - 1546"},"PeriodicalIF":0.0,"publicationDate":"2022-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77093507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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