Authors: Okamoto, Yuko¹; Tanaka, Toshimasa²; Kokubo, Hironori³

Source: Journal of Computer-Aided Molecular Design, Volume 24, Number 8, August 2010 , pp. 699-712(14)

Publisher: Springer

Abstract:

We performed replica-exchange molecular dynamics (REMD) simulations of six ligands to examine the dependency of their free energy landscapes on charge parameters and solvent models. Six different charge parameter sets for each ligand were first generated by RESP and AM1-BCC methods using three different conformations independently. RESP charges showed some conformational dependency. On the other hand, AM1-BCC charges did not show conformational dependency and well reproduced the overall trend of RESP charges. The free energy landscapes obtained from the REMD simulations of ligands in vacuum, Generalized-Born (GB), and TIP3P solutions were then analyzed. We found that even small charge differences can produce qualitatively different landscapes in vacuum condition, but the differences tend to be much smaller under GB and TIP3P conditions. The simulations in the GB model well reproduced the landscapes in the TIP3P model using only a fraction of the computational cost. The protein-bound ligand conformations were rarely the global minimum states, but similar conformations were found to exist in aqueous solution without proteins in regions close to the global minimum, local minimum or intermediate states.

Keywords: Free energy landscape; Replica-exchange molecular dynamics; RESP; AM1-BCC

Document Type: Research article

DOI: http://dx.doi.org/10.1007/s10822-010-9367-z

Affiliations: 1: Department of Physics, School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi, 464-8602, Japan 2: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 2-17-85 Juso-honmachi, Yodogawa-ku, Osaka, 532-8686, Japan 3: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 2-17-85 Juso-honmachi, Yodogawa-ku, Osaka, 532-8686, Japan, Email: kokubo_hironori@takeda.co.jp

Publication date: 2010-08-01

Related content

• In this: publication
• By this: publisher
• In this Subject: Physical & Theoretical Chemistry
• By this author: Okamoto, Yuko ;  Tanaka, Toshimasa ;  Kokubo, Hironori

Website © Publishing Technology. Article copyright remains with the publisher, society or author(s) as specified within the article.

• Terms and conditions
• Privacy policy
• Information for advertisers