Computational study of aggregation mechanism in human lysozyme[D67H].
Aggregation of proteins is an undesired phenomena that affects both human health and bioengineered products such as therapeutic proteins. Finding preventative measures could be facilitated by a molecular-level understanding of dimer formation, which is the first step in aggregation. Here we present...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5415109?pdf=render |
| _version_ | 1818319995624488960 |
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| author | Dharmeshkumar Patel Serdar Kuyucak |
| author_facet | Dharmeshkumar Patel Serdar Kuyucak |
| author_sort | Dharmeshkumar Patel |
| collection | DOAJ |
| description | Aggregation of proteins is an undesired phenomena that affects both human health and bioengineered products such as therapeutic proteins. Finding preventative measures could be facilitated by a molecular-level understanding of dimer formation, which is the first step in aggregation. Here we present a molecular dynamics (MD) study of dimer formation propensity in human lysozyme and its D67H variant. Because the latter protein aggregates while the former does not, they offer an ideal system for testing the feasibility of the proposed MD approach which comprises three stages: i) partially unfolded conformers involved in dimer formation are generated via high-temperature MD simulations, ii) potential dimer structures are searched using docking and refined with MD, iii) free energy calculations are performed to find the most stable dimer structure. Our results provide a detailed explanation for how a single mutation (D67H) turns human lysozyme from non-aggregating to an aggregating protein. Conversely, the proposed method can be used to identify the residues causing aggregation in a protein, which can be mutated to prevent it. |
| first_indexed | 2024-12-13T10:17:58Z |
| format | Article |
| id | doaj.art-c01ab0d31b0b4f2d8253c6dd919a6bfe |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T10:17:58Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-c01ab0d31b0b4f2d8253c6dd919a6bfe2022-12-21T23:51:16ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01125e017688610.1371/journal.pone.0176886Computational study of aggregation mechanism in human lysozyme[D67H].Dharmeshkumar PatelSerdar KuyucakAggregation of proteins is an undesired phenomena that affects both human health and bioengineered products such as therapeutic proteins. Finding preventative measures could be facilitated by a molecular-level understanding of dimer formation, which is the first step in aggregation. Here we present a molecular dynamics (MD) study of dimer formation propensity in human lysozyme and its D67H variant. Because the latter protein aggregates while the former does not, they offer an ideal system for testing the feasibility of the proposed MD approach which comprises three stages: i) partially unfolded conformers involved in dimer formation are generated via high-temperature MD simulations, ii) potential dimer structures are searched using docking and refined with MD, iii) free energy calculations are performed to find the most stable dimer structure. Our results provide a detailed explanation for how a single mutation (D67H) turns human lysozyme from non-aggregating to an aggregating protein. Conversely, the proposed method can be used to identify the residues causing aggregation in a protein, which can be mutated to prevent it.http://europepmc.org/articles/PMC5415109?pdf=render |
| spellingShingle | Dharmeshkumar Patel Serdar Kuyucak Computational study of aggregation mechanism in human lysozyme[D67H]. PLoS ONE |
| title | Computational study of aggregation mechanism in human lysozyme[D67H]. |
| title_full | Computational study of aggregation mechanism in human lysozyme[D67H]. |
| title_fullStr | Computational study of aggregation mechanism in human lysozyme[D67H]. |
| title_full_unstemmed | Computational study of aggregation mechanism in human lysozyme[D67H]. |
| title_short | Computational study of aggregation mechanism in human lysozyme[D67H]. |
| title_sort | computational study of aggregation mechanism in human lysozyme d67h |
| url | http://europepmc.org/articles/PMC5415109?pdf=render |
| work_keys_str_mv | AT dharmeshkumarpatel computationalstudyofaggregationmechanisminhumanlysozymed67h AT serdarkuyucak computationalstudyofaggregationmechanisminhumanlysozymed67h |