{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T10:50:57Z","timestamp":1790506257639,"version":"4.1.0"},"reference-count":52,"publisher":"AIP Publishing","issue":"8","license":[{"start":{"date-parts":[[2019,2,25]],"date-time":"2019-02-25T00:00:00Z","timestamp":1551052800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,2,25]],"date-time":"2019-02-25T00:00:00Z","timestamp":1551052800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31670727"],"award-info":[{"award-number":["31670727"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pubs.aip.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,2,28]]},"abstract":"<jats:p>Experiments have shown that cholesterol influences the membrane permeability of small molecules, amino acids, and cell-penetrating peptides. However, their exact translocation mechanisms under the influence of cholesterol remain poorly understood. Given the practical importance of cell-penetrating peptides and the existence of varied cholesterol contents in different cell types, it is necessary to examine the permeation of amino acids in cholesterol-containing membranes at atomic level of details. Here, bias-exchange metadynamics simulations were employed to investigate the molecular mechanism of the membrane permeation of two amino acids Arg and Trp important for cell-penetrating peptides in the presence of different concentrations of cholesterol. We found that the free energy barrier of Arg+ (the protonated form) permeation increased linearly as the cholesterol concentration increased, whereas the barrier of Trp permeation had a rapid increase from 0 mol. % to 20 mol. % cholesterol-containing membranes and nearly unchanged from 20 mol. % to 40 mol. % cholesterol-containing membranes. Arg0 becomes slightly more stable than Arg+ at the center of the dipalmitoylphosphatidylcholine (DPPC) membrane with 40 mol. % cholesterol concentrations. As a result, Arg+ has a similar permeability as Trp at 0 mol. % and 20 mol. % cholesterol, but a significantly lower permeability than Trp at 40 mol. % cholesterol. This difference is caused by the gradual reduction of water defects for Arg+ as the cholesterol concentration increases but lack of water defects for Trp in cholesterol-containing membranes. Strong but different orientation dependence between Arg+ and Trp permeations is observed. These results provide an improved microscopic understanding of amino-acid permeation through cholesterol-containing DPPC membrane systems.<\/jats:p>","DOI":"10.1063\/1.5082351","type":"journal-article","created":{"date-parts":[[2019,2,25]],"date-time":"2019-02-25T19:47:40Z","timestamp":1551124060000},"update-policy":"https:\/\/doi.org\/10.1063\/aip-crossmark-policy-page","source":"Crossref","is-referenced-by-count":18,"title":["Different effects of cholesterol on membrane permeation of arginine and tryptophan revealed by bias-exchange metadynamics simulations"],"prefix":"10.1063","volume":"150","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8259-0918","authenticated-orcid":false,"given":"Zanxia","family":"Cao","sequence":"first","affiliation":[{"name":"Shandong Provincial Key Laboratory of Biophysics, Institute of Biophysics, Dezhou University 1 , Dezhou 253023, China"},{"name":"College of Physics and Electronic Information, Dezhou University 2 , Dezhou 253023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiumei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Biophysics, Institute of Biophysics, Dezhou University 1 , Dezhou 253023, China"},{"name":"College of Physics and Electronic Information, Dezhou University 2 , Dezhou 253023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunling","family":"Wang","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Biophysics, Institute of Biophysics, Dezhou University 1 , Dezhou 253023, China"},{"name":"College of Physics and Electronic Information, Dezhou University 2 , Dezhou 253023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Liu","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Biophysics, Institute of Biophysics, Dezhou University 1 , Dezhou 253023, China"},{"name":"College of Information Management, Dezhou University 3 , Dezhou 253023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7375-9777","authenticated-orcid":false,"given":"Liling","family":"Zhao","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Biophysics, Institute of Biophysics, Dezhou University 1 , Dezhou 253023, China"},{"name":"College of Physics and Electronic Information, Dezhou University 2 , Dezhou 253023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihua","family":"Wang","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Biophysics, Institute of Biophysics, Dezhou University 1 , Dezhou 253023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9958-5699","authenticated-orcid":false,"given":"Yaoqi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Biophysics, Institute of Biophysics, Dezhou University 1 , Dezhou 253023, China"},{"name":"Institute for Glycomics and School of Information and Communication Technology, Griffith University 4 , Parklands Dr, Southport, QLD 4222, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"317","published-online":{"date-parts":[[2019,2,25]]},"reference":[{"key":"2023062608434394600_c1","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1038\/35080071","article-title":"How proteins move lipids and lipids move proteins","volume":"2","year":"2001","journal-title":"Nat. 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