PMID- 34856806
OWN - NLM
STAT- MEDLINE
DCOM- 20211221
LR  - 20220531
IS  - 1520-5207 (Electronic)
IS  - 1520-5207 (Linking)
VI  - 125
IP  - 49
DP  - 2021 Dec 16
TI  - N-Terminal-Driven Binding Mechanism of an Antigen Peptide to Human Leukocyte 
      Antigen-A*2402 Elucidated by Multicanonical Molecular Dynamic-Based Dynamic 
      Docking and Path Sampling Simulations.
PG  - 13376-13384
LID - 10.1021/acs.jpcb.1c07230 [doi]
AB  - We have applied our advanced multicanonical molecular dynamics (McMD)-based 
      dynamic docking methodology to investigate the binding mechanism of an HIV-1 Nef 
      protein epitope to the Asian-dominant allele human leukocyte antigen 
      (HLA)-A*2402. Even though pMHC complex formation [between a Major 
      histocompatibility complex (MHC) class I molecule, which is encoded by an HLA 
      allele, and an antigen peptide] is one of the fundamental processes of the 
      adaptive human immune response, its binding mechanism has not yet been well 
      studied, partially due to the high allelic variation of HLAs in the population. 
      We have used our developed McMD-based dynamic docking method and have 
      successfully reproduced the native complex structure, which is located near the 
      free energy global minimum. Subsequent path sampling MD simulations elucidated 
      the atomic details of the binding process and indicated that the peptide binding 
      is initially driven by the highly positively charged N-terminus of the peptide 
      that is attracted to the various negatively charged residues on the MHC 
      molecule's surface. Upon nearing the pocket, the second tyrosine residue of the 
      peptide anchors the peptide by strongly binding to the B-site of the MHC molecule 
      via hydrophobic driven interactions, resulting in a very strong bound complex 
      structure. Our methodology can be effectively used to predict the bound complex 
      structures between MHC molecules and their antigens to study their binding 
      mechanism in close detail, which would help with the development of new vaccines 
      against cancers, as well as viral infections such as HIV and COVID-19.
FAU - Bekker, Gert-Jan
AU  - Bekker GJ
AUID- ORCID: 0000-0001-8385-5693
AD  - Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 
      565-0871, Japan.
FAU - Kamiya, Narutoshi
AU  - Kamiya N
AUID- ORCID: 0000-0002-0527-6968
AD  - Graduate School of Information Science, University of Hyogo, 7-1-28 Minatojima 
      Minami-machi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211203
PL  - United States
TA  - J Phys Chem B
JT  - The journal of physical chemistry. B
JID - 101157530
RN  - 0 (HLA-A Antigens)
RN  - 0 (Peptides)
SB  - IM
MH  - HLA-A Antigens/*chemistry
MH  - Humans
MH  - *Molecular Docking Simulation
MH  - *Molecular Dynamics Simulation
MH  - Peptides
EDAT- 2021/12/04 06:00
MHDA- 2021/12/22 06:00
CRDT- 2021/12/03 05:32
PHST- 2021/12/04 06:00 [pubmed]
PHST- 2021/12/22 06:00 [medline]
PHST- 2021/12/03 05:32 [entrez]
AID - 10.1021/acs.jpcb.1c07230 [doi]
PST - ppublish
SO  - J Phys Chem B. 2021 Dec 16;125(49):13376-13384. doi: 10.1021/acs.jpcb.1c07230. 
      Epub 2021 Dec 3.