{"id":11954,"date":"2014-02-09T10:25:02","date_gmt":"2014-02-09T10:25:02","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=11954"},"modified":"2014-02-09T10:54:06","modified_gmt":"2014-02-09T10:54:06","slug":"a-congruence-of-concepts-conformations-configurations-amides-and-enzymes","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=11954","title":{"rendered":"A congruence of concepts: conformations, configurations, amides and enzymes"},"content":{"rendered":"
\n

This is the time of year when I deliver two back-2-back lecture courses, and yes I do update and revise the content! I am always on the look-out for nice new examples that illustrate how concepts and patterns in chemistry can be joined up to tell a good story. My attention is currently on conformational analysis; and here is an interesting new story to tell about it.<\/p>\n

\"atrop\"<\/a><\/p>\n

Above is a seven-membered ring benzolactam[1]<\/a><\/span>\u2021<\/sup>, and it caught my eye because of the number of concepts (the semantic density if you like) contained in its chemistry.<\/p>\n

    \n
  1. The title contains the phrase amide-based axial chirality<\/strong><\/li>\n
  2. and active <\/strong><\/li>\n
  3. conformation<\/strong><\/li>\n
  4. recognised<\/strong> by enzymes<\/strong> and receptors<\/strong><\/li>\n<\/ol>\n

    All the above also implies:<\/p>\n

      \n
    1. chirality is associated with configurations, whilst conformation is associated with isomerism about single bonds<\/li>\n
    2. when conformational analysis is transplanted into a cyclic ring, it can morph magnificently into the land of configuration, via<\/em> a process known as atropisomerism<\/a>.<\/li>\n
    3. Amides themselves sit in the land between conformation and configuration. Pauling famously used this transition<\/a> to help devise his helical structures for peptides by deducing that the apparent single N-C bond in an amide (= conformation?) is actually a partial double bond by resonance (= configuration).<\/li>\n
    4. The difference between a conformation and a configuration is simply kinetics. An approximate guideline is that if a particular pose in a system is prevented from exchanging with another pose by a half life of at least 1000 second<\/a>s, it is classified as a configuration, and if its half-life is less it is a conformation.<\/li>\n
    5. Of course enzymes and receptors recognise individual configurations, and hence respond differently. Again the vexed issue of lifetime rears its head. Thus the configuration of thalidomide<\/a> turned out to have a very short half-life, and so in vivo<\/em>, the enzymes were exposed to both configurations (one of which turned out to be toxic).<\/li>\n<\/ol>\n

      The enantiomeric equilibrium shown above for the benzolactam in fact qualifies as that for configurations, since both enantiomers can be isolated (their half-life is clearly > 1000s) and separately tested for recognition by enzymes.<\/p>\n

      How can I add any value to the above chemistry? Well, I decided to perform a search of the crystal structure database, and I added two geometric parameters;<\/p>\n

        \n
      1. The torsion about the 2-3<\/strong> bond (1-2-3-4)<\/li>\n
      2. the torsion about the 3-5<\/strong> bond (4-3-5-7).<\/li>\n<\/ol>\n

        The sign of the first is critical, since the two possible atropisomers have opposite torsion angles. The value of the second relates to Pauling’s assertion that rotation about the amide bond is indeed restricted to two values, either 0 or 180\u00b0. So these two concisely blend atropisomerism and configuration. I start with a search of the above system using just the first torsion angle. It shows a nice clustering into those with strongly -ve and those with strongly +ve values; configurational atropisomers! Of course, it does not tell us what the barrier to interconvert them is; that has to be measured (or calculated) separately.<\/p>\n

        \"7-ring-amides\"<\/a><\/p>\n

        Next, I am showing a 2D map of both torsion angles. This shows again the first distribution, but reminds us that the torsion 4-3-5<\/strong>-6 stays resolutely at ~0 for all the compounds (the amide in other words is planar).\u00a0\"7-ring-amides-heat\"<\/a><\/p>\n

        Oh, a practical point. I mentioned a calculation could be done to estimate the barrier to enantiomerising the two atropisomers. This takes hours, and days if the transition state is awkward (and atropisomers can be so). But the above plots literally took perhaps 2 minutes each! Very cheap insight!<\/p>\n

        \n

        \u2021<\/sup>Note the use of the word conformation in its title. It could equally validly be configuration! Which is better?<\/p>\n

        References<\/h2>\n
        1. H. Tabata, \"Chemistry of Amide-based Axial Chirality: Elucidation of the Active Conformation Recognized by Enzymes and Receptors\", YAKUGAKU ZASSHI<\/i>, vol. 133, pp. 857-866, 2013. https:\/\/doi.org\/10.1248\/yakushi.13-00169<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

          This is the time of year when I deliver two back-2-back lecture courses, and yes I do update and revise the content! I am always on the look-out for nice new examples that illustrate how concepts and patterns in chemistry can be joined up to tell a good story. My attention is currently on conformational […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"activitypub_content_warning":"","activitypub_content_visibility":"","activitypub_max_image_attachments":5,"activitypub_interaction_policy_quote":"anyone","activitypub_status":"","footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":true,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[1,4],"tags":[],"ppma_author":[2661],"class_list":["post-11954","post","type-post","status-publish","format-standard","hentry","category-general","category-interesting-chemistry"],"yoast_head":"\nA congruence of concepts: conformations, configurations, amides and enzymes - Henry Rzepa's Blog<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=11954\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"A congruence of concepts: conformations, configurations, amides and enzymes - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"This is the time of year when I deliver two back-2-back lecture courses, and yes I do update and revise the content! I am always on the look-out for nice new examples that illustrate how concepts and patterns in chemistry can be joined up to tell a good story. My attention is currently on conformational […]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=11954\" \/>\n<meta property=\"og:site_name\" content=\"Henry Rzepa's Blog\" \/>\n<meta property=\"article:published_time\" content=\"2014-02-09T10:25:02+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2014-02-09T10:54:06+00:00\" \/>\n<meta property=\"og:image\" content=\"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2014\/02\/atrop.svg\" \/>\n<meta name=\"author\" content=\"Henry Rzepa\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Henry Rzepa\" \/>\n\t<meta name=\"twitter:label2\" content=\"Estimated reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"3 minutes\" \/>\n<!-- \/ Yoast SEO plugin. -->","yoast_head_json":{"title":"A congruence of concepts: conformations, configurations, amides and enzymes - Henry Rzepa's Blog","robots":{"index":"index","follow":"follow","max-snippet":"max-snippet:-1","max-image-preview":"max-image-preview:large","max-video-preview":"max-video-preview:-1"},"canonical":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=11954","og_locale":"en_GB","og_type":"article","og_title":"A congruence of concepts: conformations, configurations, amides and enzymes - Henry Rzepa's Blog","og_description":"This is the time of year when I deliver two back-2-back lecture courses, and yes I do update and revise the content! I am always on the look-out for nice new examples that illustrate how concepts and patterns in chemistry can be joined up to tell a good story. My attention is currently on conformational […]","og_url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=11954","og_site_name":"Henry Rzepa's Blog","article_published_time":"2014-02-09T10:25:02+00:00","article_modified_time":"2014-02-09T10:54:06+00:00","og_image":[{"url":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2014\/02\/atrop.svg","type":"","width":"","height":""}],"author":"Henry Rzepa","twitter_card":"summary_large_image","twitter_misc":{"Written by":"Henry Rzepa","Estimated reading time":"3 minutes"},"schema":{"@context":"https:\/\/schema.org","@graph":[{"@type":"Article","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=11954#article","isPartOf":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=11954"},"author":{"name":"Henry Rzepa","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#\/schema\/person\/2b40f7b9c872a4dc1547e040a11b6281"},"headline":"A congruence of concepts: conformations, configurations, amides and enzymes","datePublished":"2014-02-09T10:25:02+00:00","dateModified":"2014-02-09T10:54:06+00:00","mainEntityOfPage":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=11954"},"wordCount":608,"commentCount":2,"image":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=11954#primaryimage"},"thumbnailUrl":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2014\/02\/atrop.svg","articleSection":["General","Interesting chemistry"],"inLanguage":"en-GB","potentialAction":[{"@type":"CommentAction","name":"Comment","target":["https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=11954#respond"]}]},{"@type":"WebPage","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=11954","url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=11954","name":"A congruence of concepts: conformations, configurations, amides and enzymes - Henry Rzepa's Blog","isPartOf":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#website"},"primaryImageOfPage":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=11954#primaryimage"},"image":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=11954#primaryimage"},"thumbnailUrl":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2014\/02\/atrop.svg","datePublished":"2014-02-09T10:25:02+00:00","dateModified":"2014-02-09T10:54:06+00:00","author":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#\/schema\/person\/2b40f7b9c872a4dc1547e040a11b6281"},"breadcrumb":{"@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=11954#breadcrumb"},"inLanguage":"en-GB","potentialAction":[{"@type":"ReadAction","target":["https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=11954"]}]},{"@type":"ImageObject","inLanguage":"en-GB","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=11954#primaryimage","url":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2014\/02\/atrop.svg","contentUrl":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2014\/02\/atrop.svg"},{"@type":"BreadcrumbList","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=11954#breadcrumb","itemListElement":[{"@type":"ListItem","position":1,"name":"Home","item":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog"},{"@type":"ListItem","position":2,"name":"A congruence of concepts: conformations, configurations, amides and enzymes"}]},{"@type":"WebSite","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#website","url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/","name":"Henry Rzepa's Blog","description":"Chemistry with a twist","potentialAction":[{"@type":"SearchAction","target":{"@type":"EntryPoint","urlTemplate":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?s={search_term_string}"},"query-input":{"@type":"PropertyValueSpecification","valueRequired":true,"valueName":"search_term_string"}}],"inLanguage":"en-GB"},{"@type":"Person","@id":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/#\/schema\/person\/2b40f7b9c872a4dc1547e040a11b6281","name":"Henry Rzepa","image":{"@type":"ImageObject","inLanguage":"en-GB","@id":"https:\/\/secure.gravatar.com\/avatar\/897b6740f7f599bca7942cdf7d7914af5988937ae0e3869ab09aebb87f26a731?s=96&d=blank&r=g370be3a7397865e4fd161aefeb0a5a85","url":"https:\/\/secure.gravatar.com\/avatar\/897b6740f7f599bca7942cdf7d7914af5988937ae0e3869ab09aebb87f26a731?s=96&d=blank&r=g","contentUrl":"https:\/\/secure.gravatar.com\/avatar\/897b6740f7f599bca7942cdf7d7914af5988937ae0e3869ab09aebb87f26a731?s=96&d=blank&r=g","caption":"Henry Rzepa"},"description":"Henry Rzepa is Emeritus Professor of Computational Chemistry at Imperial College London.","sameAs":["https:\/\/orcid.org\/0000-0002-8635-8390"],"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?author=1"}]}},"jetpack_publicize_connections":[],"jetpack_featured_media_url":"","jetpack_sharing_enabled":true,"jetpack_shortlink":"https:\/\/wp.me\/pDef7-36O","jetpack-related-posts":[{"id":1174,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=1174","url_meta":{"origin":11954,"position":0},"title":"The Fine-tuned principle in chemistry","author":"Henry Rzepa","date":"November 29, 2009","format":false,"excerpt":"The \u00a0so-called \u00a0Fine tuned model of the universe asserts that any small change in several of the\u00a0dimensionless fundamental physical constants would make the universe radically different (and hence one in which life as we know it could not exist). I suggest here that there may be molecules which epitomize the\u2026","rel":"","context":"In "Interesting chemistry"","block_context":{"text":"Interesting chemistry","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=4"},"img":{"alt_text":"Dimethyl formamide","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/11\/dmf.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":6044,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=6044","url_meta":{"origin":11954,"position":1},"title":"Secrets of a university tutor: tetrahedral intermediates.","author":"Henry Rzepa","date":"January 8, 2012","format":false,"excerpt":"The tetrahedral intermediate is one of those iconic species on which the foundation of reaction mechanism in organic chemistry is built. It refers to a (normally undetected and hence merely inferred) species formed initially when a nucleophilic reagent attacks a carbonyl compound. Its importance to understanding the activity of enzymes\u2026","rel":"","context":"In "Interesting chemistry"","block_context":{"text":"Interesting chemistry","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=4"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/01\/acetylcyanide.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":18318,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=18318","url_meta":{"origin":11954,"position":2},"title":"Conference report: OPEN SCIENCE AND THE CHEMISTRY LAB OF THE FUTURE","author":"Henry Rzepa","date":"May 23, 2017","format":false,"excerpt":"This is taking place in the idyllic surroundings of the Niederwald forest, R\u00fcdesheim, Germany. Here I highlight only aspects of the first three talks. Martin Hicks introduced the conference with concepts such as the global public good. In the area of open access, he reminded us of the terms Platinum\/Diamond\u2026","rel":"","context":"In "Chemical IT"","block_context":{"text":"Chemical IT","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=2"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2017\/05\/IMG_1672.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2017\/05\/IMG_1672.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2017\/05\/IMG_1672.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":19433,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=19433","url_meta":{"origin":11954,"position":3},"title":"Is (h\u03bd)3 an allotrope of light?","author":"Henry Rzepa","date":"February 23, 2018","format":false,"excerpt":"A little while ago I pondered allotropic bromine, or Br(Br)3. But this is a far wackier report of a molecule of light. The preparation and detection of dimer and trimer bound photon states is pure physics; probably considered by the physicists themselves as NOT chemistry. It is certainly true, as\u2026","rel":"","context":"In "Interesting chemistry"","block_context":{"text":"Interesting chemistry","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=4"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":17311,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=17311","url_meta":{"origin":11954,"position":4},"title":"The “hydrogen bond”; its early history.","author":"Henry Rzepa","date":"December 31, 2016","format":false,"excerpt":"My holiday reading has been Derek Lowe's excellent\u00a0Chemistry Book setting out 250 milestones in chemistry, organised by year. An\u00a0entry for 1920 entitled hydrogen bonding\u00a0seemed worth exploring in more detail here. As with many historical concepts, it can often take a few years to coalesce into something we would readily recognise\u2026","rel":"","context":"In "Historical"","block_context":{"text":"Historical","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=565"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2016\/12\/066-1024x91.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":17122,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=17122","url_meta":{"origin":11954,"position":5},"title":"Long C=C bonds.","author":"Henry Rzepa","date":"December 1, 2016","format":false,"excerpt":"Following on from a search for long C-C bonds, here is the same repeated for C=C double bonds. The query restricts the search to each carbon having just two non-metallic substituents. To avoid conjugation with these, they each are 4-coordinated; the carbons themselves are three-coordinated. Further constraints are the usual\u2026","rel":"","context":"In "crystal_structure_mining"","block_context":{"text":"crystal_structure_mining","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=1745"},"img":{"alt_text":"sq","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2016\/12\/sq-1024x415.jpg?resize=350%2C200","width":350,"height":200},"classes":[]}],"jetpack_likes_enabled":false,"authors":[{"term_id":2661,"user_id":1,"is_guest":0,"slug":"admin","display_name":"Henry Rzepa","avatar_url":"https:\/\/secure.gravatar.com\/avatar\/897b6740f7f599bca7942cdf7d7914af5988937ae0e3869ab09aebb87f26a731?s=96&d=blank&r=g","0":null,"1":"","2":"","3":"","4":"","5":"","6":"","7":"","8":""}],"_links":{"self":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/11954","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=11954"}],"version-history":[{"count":8,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/11954\/revisions"}],"predecessor-version":[{"id":11963,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/11954\/revisions\/11963"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=11954"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=11954"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=11954"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=11954"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}