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Therefore, a firm understanding of their conformational preferences is important for drug design. Given the importance of macrocycle-protein modelling in drug discovery, we envisaged that a systematic study of both classical and recent specialized methods would provide guidance for other practitioners within the field. In this study we compare the performance of the general, well established conformational analysis methods Monte Carlo Multiple Minimum (MCMM) and Mixed Torsional\/Low-Mode sampling (MTLMOD) with two more recent and specialized macrocycle sampling techniques: MacroModel macrocycle Baseline Search (MD\/LLMOD) and Prime macrocycle conformational sampling (PRIME-MCS). Using macrocycles extracted from 44 macrocycle-protein X-ray crystallography complexes, we evaluated each method based on their ability to (i) generate unique conformers, (ii) generate unique macrocycle ring conformations, (iii) identify the global energy minimum, (iv) identify conformers similar to the X-ray ligand conformation after Protein Preparation Wizard treatment (X-ray\n                      <jats:sub>ppw<\/jats:sub>\n                      ), and (v) to the X-ray\n                      <jats:sub>ppw<\/jats:sub>\n                      ring conformation. Computational speed was also considered. In addition, conformational coverage, as defined by the number of conformations identified, was studied. In order to study the relative energies of the bioactive conformations, the energy differences between the global energy minima and the energy minimized X-ray\n                      <jats:sub>ppw<\/jats:sub>\n                      structures and, the global energy minima and the MCMM-Exhaustive (1,000,000 search steps) generated conformers closest to the X-ray\n                      <jats:sub>ppw<\/jats:sub>\n                      structure, were calculated and analysed. All searches were performed using relatively short run times (10,000 steps for MCMM, MTLMOD and MD\/LLMOD). To assess the performance of the methods, they were compared to an exhaustive MCMM search using 1,000,000 search steps for each of the 44 macrocycles (requiring ca 200 times more CPU time). Prior to our analysis, we also investigated if the general search methods MCMM and MTLMOD could also be optimized for macrocycle conformational sampling. Taken together, our work concludes that the more general methods can be optimized for macrocycle modelling by slightly adjusting the settings around the ring closure bond. In most cases, MCMM and MTLMOD with either standard or enhanced settings performed well in comparison to the more specialized macrocycle sampling methods MD\/LLMOD and PRIME-MCS. When using enhanced settings for MCMM and MTLMOD, the X-ray\n                      <jats:sub>ppw<\/jats:sub>\n                      conformation was regenerated with the greatest accuracy. The, MD\/LLMOD emerged as the most efficient method for generating the global energy minima.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphic abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s10822-020-00277-2","type":"journal-article","created":{"date-parts":[[2020,1,21]],"date-time":"2020-01-21T01:03:56Z","timestamp":1579568636000},"page":"231-252","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Conformational analysis of macrocycles: comparing general and specialized methods"],"prefix":"10.1007","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4713-8368","authenticated-orcid":false,"given":"Gustav","family":"Olanders","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiba","family":"Alogheli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2885-2016","authenticated-orcid":false,"given":"Peter","family":"Brandt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9512-6981","authenticated-orcid":false,"given":"Anders","family":"Karl\u00e9n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,21]]},"reference":[{"key":"277_CR1","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1124\/pr.112.007336","volume":"66","author":"G Sliwoski","year":"2014","unstructured":"Sliwoski G, Kothiwale S, Meiler J, Lowe EW Jr (2014) Computational methods in drug discovery. 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