{"id":248,"date":"2009-04-12T12:00:36","date_gmt":"2009-04-12T11:00:36","guid":{"rendered":"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=248"},"modified":"2011-11-29T15:15:32","modified_gmt":"2011-11-29T15:15:32","slug":"248","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=248","title":{"rendered":"Conformational analysis and enzyme activity: models for amide hydrolysis."},"content":{"rendered":"<div class=\"kcite-section\" kcite-section-id=\"248\">\n<p>The diagram below summarizes an interesting result recently reported by Hanson and co-workers (DOI: <a href=\"http:\/\/dx.doi.org\/10.1021\/jo800706y\" target=\"new\">10.1021\/jo800706y<\/a>. At ~neutral pH, compound <strong>13<\/strong> hydrolyses with a half life of 21 minutes, whereas <strong>14<\/strong> takes 840 minutes. Understanding this difference in reactivity may allow us to understand why some enzymes can catalyze the hydrolysis of peptides with an acceleration of up to twelve orders of magnitude.<\/p>\n<div id=\"attachment_247\" style=\"width: 510px\" class=\"wp-caption aligncenter\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-247\" class=\"size-full wp-image-247\" title=\"amide-cleavage\" src=\"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/04\/amide-cleavage.png\" alt=\"Models for peptide cleavage.\" width=\"500\" height=\"311\" \/><p id=\"caption-attachment-247\" class=\"wp-caption-text\">Models for peptide cleavage.<\/p><\/div>\n<p>The secret to understanding this behaviour lies in a technique known as <strong>conformational analysis<\/strong>, for which Derek Barton was awarded a Nobel prize. Indeed, the very molecules for which he first developed his technique were the decalins, of which molecule \u00a0<strong>13<\/strong> is an example of a <em>cis<\/em>-decalin and <strong>14<\/strong> a <em>trans<\/em>-decalin. Barton&#8217;s insight was to recognize that both types of ring prefer to exist in chair conformations rather than the alternative boat shape.<\/p>\n<p>The technique pioneered by Barton for estimating the energies of these various conformations is called <strong>Molecular Mechanics<\/strong>, and can be used to explain the difference in reactivity. Considering first molecule <strong>13<\/strong>, one can calculate its molecular mechanics energy for two conformations, differing in whether the N-alkyl sidechain is equatorial (left) or axial (right).<\/p>\n<p><div id=\"attachment_261\" style=\"width: 376px\" class=\"wp-caption aligncenter\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-261\" class=\"size-full wp-image-261\" title=\"peptide-cis1\" onclick=\"jmolInitialize('..\/Jmol\/');jmolSetAppletColor('yellow');jmolApplet([450,450],'load wp-content\/uploads\/2009\/04\/peptide-13.3.mol;zoom 120;spin 3;');\" src=\"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/04\/peptide-cis1.jpg\" alt=\"Cis amide\" width=\"366\" height=\"192\" \/><p id=\"caption-attachment-261\" class=\"wp-caption-text\">Cis amide. Click for Equatorial 3D.<\/p><\/div>The equatorial form (green box) comes out about 5 kcal\/mol lower in energy than the axial (red box). One can also calculate the energy of the product, which arises from the OH attacking the carbon of the amide (dashed lines), evicting ammonia, and forming a cyclic lactone. Here, the most stable product (by ~10 kcal\/mol) is again that resulting from the green bond forming. From the simple relationship \u0394G = -RT Ln K (where K describes the position of the equatorial\/axial equilibrium), one can conclude that the ratio <em>equatorial\/axial<\/em>is ~4000, i.e. the favoured reaction arises from the most abundant reactant.<\/p>\n<p><div id=\"attachment_259\" style=\"width: 398px\" class=\"wp-caption aligncenter\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-259\" class=\"size-full wp-image-259\" title=\"peptide-trans\" onclick=\"jmolInitialize('..\/Jmol\/');jmolSetAppletColor('yellow');jmolApplet([450,450],'load wp-content\/uploads\/2009\/04\/peptide-trans-8.9.mol;zoom 120;spin 3;');\" src=\"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/04\/peptide-trans.jpg\" alt=\"Trans amide\" width=\"388\" height=\"158\" \/><p id=\"caption-attachment-259\" class=\"wp-caption-text\">Trans amide. Click for 3D.<\/p><\/div>With the <em>trans<\/em> amide, the equatorial conformation (green box) is around 3 kcal\/mol lower than the axial (red box), but now the most stable lactone product (by ~ 3 kcal\/mol) arises (green bond) from the <strong>less stable<\/strong>axial reactant. For reaction to occur, the equatorial reactant has to first isomerise to the axial, which imposes a ~3 kcal\/mol penalty on the reaction. This is enough to slow the rate of the reaction significantly compared to the un-penalised cis-decalin reaction.<\/p>\n<p>&nbsp;<\/p>\n<!-- kcite active, but no citations found -->\n<\/div> <!-- kcite-section 248 -->","protected":false},"excerpt":{"rendered":"<p>The diagram below summarizes an interesting result recently reported by Hanson and co-workers (DOI: 10.1021\/jo800706y. At ~neutral pH, compound 13 hydrolyses with a half life of 21 minutes, whereas 14 takes 840 minutes. Understanding this difference in reactivity may allow us to understand why some enzymes can catalyze the hydrolysis of peptides with an acceleration [&hellip;]<\/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":false,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[4],"tags":[48,17,46,24,47,2648,44,45,43],"ppma_author":[2661],"class_list":["post-248","post","type-post","status-publish","format-standard","hentry","category-interesting-chemistry","tag-chair","tag-conformational-analysis","tag-derek-barton","tag-energy","tag-hanson","tag-interesting-chemistry","tag-molecular-mechanics-energy","tag-stable-lactone-product","tag-stable-product"],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.3 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Conformational analysis and enzyme activity: models for amide hydrolysis. - Henry Rzepa&#039;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=248\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Conformational analysis and enzyme activity: models for amide hydrolysis. - Henry Rzepa&#039;s Blog\" \/>\n<meta property=\"og:description\" content=\"The diagram below summarizes an interesting result recently reported by Hanson and co-workers (DOI: 10.1021\/jo800706y. At ~neutral pH, compound 13 hydrolyses with a half life of 21 minutes, whereas 14 takes 840 minutes. Understanding this difference in reactivity may allow us to understand why some enzymes can catalyze the hydrolysis of peptides with an acceleration [&hellip;]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=248\" \/>\n<meta property=\"og:site_name\" content=\"Henry Rzepa&#039;s Blog\" \/>\n<meta property=\"article:published_time\" content=\"2009-04-12T11:00:36+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2011-11-29T15:15:32+00:00\" \/>\n<meta property=\"og:image\" content=\"http:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/04\/amide-cleavage.png\" \/>\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=\"2 minutes\" \/>\n<!-- \/ Yoast SEO plugin. -->","yoast_head_json":{"title":"Conformational analysis and enzyme activity: models for amide hydrolysis. - Henry Rzepa&#039;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=248","og_locale":"en_GB","og_type":"article","og_title":"Conformational analysis and enzyme activity: models for amide hydrolysis. - Henry Rzepa&#039;s Blog","og_description":"The diagram below summarizes an interesting result recently reported by Hanson and co-workers (DOI: 10.1021\/jo800706y. 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