{"id":2441,"date":"2015-06-08T16:10:51","date_gmt":"2015-06-08T15:10:51","guid":{"rendered":"http:\/\/www.blopig.com\/blog\/?p=2441"},"modified":"2015-06-08T20:28:19","modified_gmt":"2015-06-08T19:28:19","slug":"investigating-structural-mechanisms-with-customised-natural-moves","status":"publish","type":"post","link":"https:\/\/www.blopig.com\/blog\/2015\/06\/investigating-structural-mechanisms-with-customised-natural-moves\/","title":{"rendered":"Investigating structural mechanisms with customised Natural Moves"},"content":{"rendered":"

This is a brief overview of my current work on a protocol for studying molecular mechanisms in biomolecules. It is based on Natural Move Monte Carlo (NMMC)<\/a>, a technique pioneered by one of my supervisors,\u00a0Peter Minary<\/a>.<\/p>\n

NMMC\u00a0allows the user to decompose a protein or nucleic acid\u00a0structure into segments\u00a0of atoms\/residues. Each segment is moved collectively and treated as a single body. This gives rise to a sampling strategy that considers the structure as a fluid of segments and probes the different arrangements in a Monte Carlo fashion.<\/p>\n

Traditionally the initial decomposition would be the only one that is sampled.\u00a0However, this decomposition might not always be optimal. Critical degrees of freedom\u00a0might have been missed out or chosen sub-optimally. Additionally, if we want\u00a0to test\u00a0the causality of a structural\u00a0mechanism it can be\u00a0informative to perform NMMC simulations for a variety of decompositions. Here I show an example of how customised Natural Moves may be\u00a0applied on a DNA system.<\/p>\n

\n

Investigating the effect of epigenetic marks on the structure of a DNA toy model<\/h2>\n
\"epigeneticsintro\"<\/a>

Figure 1. Three levels at which epigenetic activity takes place. Figure adopted from Charles C. Matouk, and Philip A. Marsden Circulation Research. 2008;102:873-887<\/p><\/div>\n

Epigenetic marks on DNA nucleotides are involved in regulating gene\u00a0expression (Point 1 in figure 1). We have a limited understanding of the underlying molecular mechanism of this process. There are two mechanisms that are thought to be involved: 1) Direct recognition of the epigenetic mark by DNA binding proteins and 2) indirect recognition of changes in\u00a0the local DNA structure caused by the epigenetic mark. Using customised Natural Moves we are currently trying to\u00a0to gain insight into these\u00a0mechanisms.<\/p>\n

One type of epigenetic mark is the 5-hydroxymethylation (5hm) on cytosines. Lercher et al.<\/a> have recently solved a crystal structure of the Drew-Dickerson Dodecamer with two of these epigenetic marks attached. Given the right sequence context (e.g. CpG) they have found that this epigenetic mark\u00a0can form a\u00a0hydrogen bond between two neighbouring bases on the same strand. This raises the question: Can an\u00a0intra-strand CpG hydrogen bond alter the DNA helical parameters?\u00a0We used this as a toy model to test our technology.<\/p>\n

\"cDOFsSchematic\"<\/a>

Figure 2b<\/p><\/div>\n

\"dna_schematic\"<\/a>

Figure 2a<\/p><\/div>\n

Figure 2a shows the Drew-Dickerson Dodecamer schematically.\u00a0Figure 2b shows the three sets of degrees of freedom that we used as test cases.<\/p>\n

Top (11)<\/em>: Default sampling – Serves as a reference simulation.
\nMiddle\u00a0(01)<\/em>: Fixed 5hm torsions – By forcing the hydroxyl group of 5hmC towards the guanine we significantly increase\u00a0the chance of the hydrogen bond forming.
\nBottom\u00a0(00)<\/em>: Collective movement of the neighbouring bases 5hmC and G – By grouping the two bases into a segment we aim to emulate\u00a0the dampening\u00a0effect that a hydrogen bond may have on their movements\u00a0relative to each other.<\/p>\n

By modifying\u00a0these degrees of freedom (1=active\/ 0=inactive) we attempted to amplify any effects that the CpG hydrogen bond may have on the DNA structure.<\/p>\n

Below you can see animations\u00a0of the three test cases 11, 01, 00\u00a0during simulation, zoomed in on the 5hm modification and the neighbouring base pair:<\/p>\n

\"full\"<\/a>\"fullfixedCHM\"<\/a>\"fullfixedGC\"<\/a><\/p>\n

\n

It appeared that the default degrees of freedom were not sufficient to detect a change in the DNA structure when comparing simulations of unmodified and modified structures.\u00a0The other two test cases with customised Natural Moves, however, showed alterations in some of the helical parameters.<\/p>\n

Lercher et al. saw no differences in their modified and unmodified crystal structures. It seems that single 5hm epigenetic marks are not sufficient to significantly alter DNA structure. Rather, clusters of these modifications with accumulated structural effects may be required to cause\u00a0significant changes in DNA\u00a0helical parameters. CpG islands may be\u00a0a promising candidate.<\/p>\n

@samdemharter<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"

This is a brief overview of my current work on a protocol for studying molecular mechanisms in biomolecules. It is based on Natural Move Monte Carlo (NMMC), a technique pioneered by one of my supervisors,\u00a0Peter Minary. NMMC\u00a0allows the user to decompose a protein or nucleic acid\u00a0structure into segments\u00a0of atoms\/residues. Each segment is moved collectively and […]<\/p>\n","protected":false},"author":29,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"nf_dc_page":"","wikipediapreview_detectlinks":true,"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"ngg_post_thumbnail":0,"_jetpack_memberships_contains_paid_content":false,"footnotes":""},"categories":[1],"tags":[],"ppma_author":[519],"class_list":["post-2441","post","type-post","status-publish","format-standard","hentry","category-uncategorized"],"jetpack_featured_media_url":"","jetpack_sharing_enabled":true,"authors":[{"term_id":519,"user_id":29,"is_guest":0,"slug":"samuel","display_name":"Samuel Demharter","avatar_url":"https:\/\/secure.gravatar.com\/avatar\/9a7fc311ca91aec48d77ebd689fe2070f28c5442207cffd3adbd026c24de4d17?s=96&d=mm&r=g","0":null,"1":"","2":"","3":"","4":"","5":"","6":"","7":"","8":""}],"_links":{"self":[{"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/posts\/2441","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/users\/29"}],"replies":[{"embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/comments?post=2441"}],"version-history":[{"count":16,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/posts\/2441\/revisions"}],"predecessor-version":[{"id":2489,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/posts\/2441\/revisions\/2489"}],"wp:attachment":[{"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/media?parent=2441"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/categories?post=2441"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/tags?post=2441"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/ppma_author?post=2441"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}