Molecular Structure Refinement Based on Residual Dipolar Couplings: A Comparison of the Molecular Rotational-Sampling Method with the Alignment-Tensor Approach
In NMR experiments, residual dipolar couplings (RDCs) in a molecule can be measured by averaging the dipolar couplings (DCs) over the rotational motion of a molecule in an environment that induces a slight anisotropic orientation distribution of the molecule. Since the shape of the anisotropic distr...
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description | In NMR experiments, residual dipolar couplings (RDCs) in a molecule can be measured by averaging the dipolar couplings (DCs) over the rotational motion of a molecule in an environment that induces a slight anisotropic orientation distribution of the molecule. Since the shape of the anisotropic distribution cannot be measured, it is standard practice to use a particular orientation distribution of the molecule with respect to the magnetic field, in the form of a so-called alignment tensor (AT), to calculate RDC-values for the molecule. Since the same alignment tensor is commonly used to calculate the different RDCs of a molecule, this approach rests on the assumption that the rotational motion of the molecule is decoupled from its internal motions and that the molecule is rigid. The validity of these two assumptions is investigated for a small, simple molecule, using a relatively rigid atomic interaction function or force field and a more flexible one. By simulating the molecule using an orientation-biasing force an anisotropic rotational distribution can be generated, for which RDCs can be obtained. Using these RDCs as target RDCs when applying one of the two approaches of structure refinement based on RDCs, it can be investigated how well the target RDCs are approximated in the RDC restraining and whether the corresponding nonuniform orientation distribution is reproduced. For the relatively rigid version of the molecule, the AT approach reproduces the target RDC-values, although the nonuniform orientation distribution of the angle θ ab,H between the vector r⃗ ab connecting two atoms a and b in the molecule and the vector representing the direction of the magnetic field H⃗ as generated in the orientation-biasing simulation cannot be reproduced in the AT RDC-restraining simulation. For the relatively flexible version of the molecule, the AT approach fails to reproduce both the target RDC values and the nonuniform orientation distribution. For biomolecules with flexible parts, the application of the AT approach is thus not recommended. Instead, a method based on sampling of the rotational and internal degrees of freedom of the molecule should be applied in molecular structure determination or refinement based on measured RDCs. |
doi_str_mv | 10.1021/acs.jcim.4c00416 |
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Since the shape of the anisotropic distribution cannot be measured, it is standard practice to use a particular orientation distribution of the molecule with respect to the magnetic field, in the form of a so-called alignment tensor (AT), to calculate RDC-values for the molecule. Since the same alignment tensor is commonly used to calculate the different RDCs of a molecule, this approach rests on the assumption that the rotational motion of the molecule is decoupled from its internal motions and that the molecule is rigid. The validity of these two assumptions is investigated for a small, simple molecule, using a relatively rigid atomic interaction function or force field and a more flexible one. By simulating the molecule using an orientation-biasing force an anisotropic rotational distribution can be generated, for which RDCs can be obtained. Using these RDCs as target RDCs when applying one of the two approaches of structure refinement based on RDCs, it can be investigated how well the target RDCs are approximated in the RDC restraining and whether the corresponding nonuniform orientation distribution is reproduced. For the relatively rigid version of the molecule, the AT approach reproduces the target RDC-values, although the nonuniform orientation distribution of the angle θ ab,H between the vector r⃗ ab connecting two atoms a and b in the molecule and the vector representing the direction of the magnetic field H⃗ as generated in the orientation-biasing simulation cannot be reproduced in the AT RDC-restraining simulation. For the relatively flexible version of the molecule, the AT approach fails to reproduce both the target RDC values and the nonuniform orientation distribution. For biomolecules with flexible parts, the application of the AT approach is thus not recommended. Instead, a method based on sampling of the rotational and internal degrees of freedom of the molecule should be applied in molecular structure determination or refinement based on measured RDCs.</description><identifier>ISSN: 1549-9596</identifier><identifier>ISSN: 1549-960X</identifier><identifier>EISSN: 1549-960X</identifier><identifier>DOI: 10.1021/acs.jcim.4c00416</identifier><identifier>PMID: 38861396</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Alignment ; Anisotropy ; Atomic interactions ; Biomolecules ; Computational Biochemistry ; Constraining ; Couplings ; Magnetic fields ; Magnetic Resonance Spectroscopy - methods ; Models, Molecular ; Molecular structure ; NMR ; Nuclear magnetic resonance ; Orientation ; Rotation ; Sampling methods ; Tensors</subject><ispartof>Journal of chemical information and modeling, 2024-06, Vol.64 (12), p.4781-4801</ispartof><rights>2024 American Chemical Society</rights><rights>Copyright American Chemical Society Jun 24, 2024</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-a247t-8b83b362cc8ddcfe7345f5f7868d10ef7a57e667edfe8da970288427b41f11783</cites><orcidid>0000-0002-1615-5600 ; 0000-0002-9583-7019 ; 0000-0003-4366-6120 ; 0000-0001-5040-9267</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jcim.4c00416$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jcim.4c00416$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38861396$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pechlaner, Maria</creatorcontrib><creatorcontrib>van Gunsteren, Wilfred F.</creatorcontrib><creatorcontrib>Smith, Lorna J.</creatorcontrib><creatorcontrib>Stankiewicz, Bartosz</creatorcontrib><creatorcontrib>Wirz, Lukas N.</creatorcontrib><creatorcontrib>Hansen, Niels</creatorcontrib><title>Molecular Structure Refinement Based on Residual Dipolar Couplings: A Comparison of the Molecular Rotational-Sampling Method with the Alignment-Tensor Approach</title><title>Journal of chemical information and modeling</title><addtitle>J. Chem. Inf. Model</addtitle><description>In NMR experiments, residual dipolar couplings (RDCs) in a molecule can be measured by averaging the dipolar couplings (DCs) over the rotational motion of a molecule in an environment that induces a slight anisotropic orientation distribution of the molecule. Since the shape of the anisotropic distribution cannot be measured, it is standard practice to use a particular orientation distribution of the molecule with respect to the magnetic field, in the form of a so-called alignment tensor (AT), to calculate RDC-values for the molecule. Since the same alignment tensor is commonly used to calculate the different RDCs of a molecule, this approach rests on the assumption that the rotational motion of the molecule is decoupled from its internal motions and that the molecule is rigid. The validity of these two assumptions is investigated for a small, simple molecule, using a relatively rigid atomic interaction function or force field and a more flexible one. By simulating the molecule using an orientation-biasing force an anisotropic rotational distribution can be generated, for which RDCs can be obtained. Using these RDCs as target RDCs when applying one of the two approaches of structure refinement based on RDCs, it can be investigated how well the target RDCs are approximated in the RDC restraining and whether the corresponding nonuniform orientation distribution is reproduced. For the relatively rigid version of the molecule, the AT approach reproduces the target RDC-values, although the nonuniform orientation distribution of the angle θ ab,H between the vector r⃗ ab connecting two atoms a and b in the molecule and the vector representing the direction of the magnetic field H⃗ as generated in the orientation-biasing simulation cannot be reproduced in the AT RDC-restraining simulation. For the relatively flexible version of the molecule, the AT approach fails to reproduce both the target RDC values and the nonuniform orientation distribution. For biomolecules with flexible parts, the application of the AT approach is thus not recommended. Instead, a method based on sampling of the rotational and internal degrees of freedom of the molecule should be applied in molecular structure determination or refinement based on measured RDCs.</description><subject>Alignment</subject><subject>Anisotropy</subject><subject>Atomic interactions</subject><subject>Biomolecules</subject><subject>Computational Biochemistry</subject><subject>Constraining</subject><subject>Couplings</subject><subject>Magnetic fields</subject><subject>Magnetic Resonance Spectroscopy - methods</subject><subject>Models, Molecular</subject><subject>Molecular structure</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Orientation</subject><subject>Rotation</subject><subject>Sampling methods</subject><subject>Tensors</subject><issn>1549-9596</issn><issn>1549-960X</issn><issn>1549-960X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kUuLFDEUhYMozji6dyUBNy6sNkmlKil3bfuEGYSZEdwV6dTNdJpUpSYPxF_jXzX9UhBc3XvDd84hHISeU7KghNE3SsfFVttxwTUhnLYP0DlteFd1Lfn-8LQ3XXuGnsS4JaSuu5Y9Rme1lC0t-zn6deUd6OxUwDcpZJ1yAHwNxk4wwpTwOxVhwH4qb9EOWTn83s5-h698np2d7uJbvCzHOKtgYwG9wWkD-K_vtU8qWT8pV92oca_BV5A2fsA_bNrs6aWzd9MusLqFKfqAl_McvNKbp-iRUS7Cs-O8QN8-frhdfa4uv376slpeVopxkSq5lvW6bpnWchi0AVHzxjRGyFYOlIARqhHQtgIGA3JQnSBMSs7EmlNDqZD1BXp18C2x9xli6kcbNTinJvA59jURtCG8YbygL_9Btz6H8r09xQhlpGGFIgdKBx9jANPPwY4q_Owp6Xfl9aW8fldefyyvSF4cjfN6hOGP4NRWAV4fgL30FPpfv9-XbagM</recordid><startdate>20240624</startdate><enddate>20240624</enddate><creator>Pechlaner, Maria</creator><creator>van Gunsteren, Wilfred F.</creator><creator>Smith, Lorna J.</creator><creator>Stankiewicz, Bartosz</creator><creator>Wirz, Lukas N.</creator><creator>Hansen, Niels</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7SC</scope><scope>7SR</scope><scope>7U5</scope><scope>8BQ</scope><scope>8FD</scope><scope>JG9</scope><scope>JQ2</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-1615-5600</orcidid><orcidid>https://orcid.org/0000-0002-9583-7019</orcidid><orcidid>https://orcid.org/0000-0003-4366-6120</orcidid><orcidid>https://orcid.org/0000-0001-5040-9267</orcidid></search><sort><creationdate>20240624</creationdate><title>Molecular Structure Refinement Based on Residual Dipolar Couplings: A Comparison of the Molecular Rotational-Sampling Method with the Alignment-Tensor Approach</title><author>Pechlaner, Maria ; van Gunsteren, Wilfred F. ; Smith, Lorna J. ; Stankiewicz, Bartosz ; Wirz, Lukas N. ; Hansen, Niels</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a247t-8b83b362cc8ddcfe7345f5f7868d10ef7a57e667edfe8da970288427b41f11783</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Alignment</topic><topic>Anisotropy</topic><topic>Atomic interactions</topic><topic>Biomolecules</topic><topic>Computational Biochemistry</topic><topic>Constraining</topic><topic>Couplings</topic><topic>Magnetic fields</topic><topic>Magnetic Resonance Spectroscopy - methods</topic><topic>Models, Molecular</topic><topic>Molecular structure</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Orientation</topic><topic>Rotation</topic><topic>Sampling methods</topic><topic>Tensors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pechlaner, Maria</creatorcontrib><creatorcontrib>van Gunsteren, Wilfred F.</creatorcontrib><creatorcontrib>Smith, Lorna J.</creatorcontrib><creatorcontrib>Stankiewicz, Bartosz</creatorcontrib><creatorcontrib>Wirz, Lukas N.</creatorcontrib><creatorcontrib>Hansen, Niels</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Computer and Information Systems Abstracts</collection><collection>Engineered Materials Abstracts</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Materials Research Database</collection><collection>ProQuest Computer Science Collection</collection><collection>Advanced Technologies Database with Aerospace</collection><collection>Computer and Information Systems Abstracts Academic</collection><collection>Computer and Information Systems Abstracts Professional</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of chemical information and modeling</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pechlaner, Maria</au><au>van Gunsteren, Wilfred F.</au><au>Smith, Lorna J.</au><au>Stankiewicz, Bartosz</au><au>Wirz, Lukas N.</au><au>Hansen, Niels</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Molecular Structure Refinement Based on Residual Dipolar Couplings: A Comparison of the Molecular Rotational-Sampling Method with the Alignment-Tensor Approach</atitle><jtitle>Journal of chemical information and modeling</jtitle><addtitle>J. Chem. Inf. Model</addtitle><date>2024-06-24</date><risdate>2024</risdate><volume>64</volume><issue>12</issue><spage>4781</spage><epage>4801</epage><pages>4781-4801</pages><issn>1549-9596</issn><issn>1549-960X</issn><eissn>1549-960X</eissn><abstract>In NMR experiments, residual dipolar couplings (RDCs) in a molecule can be measured by averaging the dipolar couplings (DCs) over the rotational motion of a molecule in an environment that induces a slight anisotropic orientation distribution of the molecule. Since the shape of the anisotropic distribution cannot be measured, it is standard practice to use a particular orientation distribution of the molecule with respect to the magnetic field, in the form of a so-called alignment tensor (AT), to calculate RDC-values for the molecule. Since the same alignment tensor is commonly used to calculate the different RDCs of a molecule, this approach rests on the assumption that the rotational motion of the molecule is decoupled from its internal motions and that the molecule is rigid. The validity of these two assumptions is investigated for a small, simple molecule, using a relatively rigid atomic interaction function or force field and a more flexible one. By simulating the molecule using an orientation-biasing force an anisotropic rotational distribution can be generated, for which RDCs can be obtained. Using these RDCs as target RDCs when applying one of the two approaches of structure refinement based on RDCs, it can be investigated how well the target RDCs are approximated in the RDC restraining and whether the corresponding nonuniform orientation distribution is reproduced. For the relatively rigid version of the molecule, the AT approach reproduces the target RDC-values, although the nonuniform orientation distribution of the angle θ ab,H between the vector r⃗ ab connecting two atoms a and b in the molecule and the vector representing the direction of the magnetic field H⃗ as generated in the orientation-biasing simulation cannot be reproduced in the AT RDC-restraining simulation. For the relatively flexible version of the molecule, the AT approach fails to reproduce both the target RDC values and the nonuniform orientation distribution. For biomolecules with flexible parts, the application of the AT approach is thus not recommended. Instead, a method based on sampling of the rotational and internal degrees of freedom of the molecule should be applied in molecular structure determination or refinement based on measured RDCs.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>38861396</pmid><doi>10.1021/acs.jcim.4c00416</doi><tpages>21</tpages><orcidid>https://orcid.org/0000-0002-1615-5600</orcidid><orcidid>https://orcid.org/0000-0002-9583-7019</orcidid><orcidid>https://orcid.org/0000-0003-4366-6120</orcidid><orcidid>https://orcid.org/0000-0001-5040-9267</orcidid></addata></record> |
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subjects | Alignment Anisotropy Atomic interactions Biomolecules Computational Biochemistry Constraining Couplings Magnetic fields Magnetic Resonance Spectroscopy - methods Models, Molecular Molecular structure NMR Nuclear magnetic resonance Orientation Rotation Sampling methods Tensors |
title | Molecular Structure Refinement Based on Residual Dipolar Couplings: A Comparison of the Molecular Rotational-Sampling Method with the Alignment-Tensor Approach |
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