From chemistry-request(+ at +)ccl.net Tue Jan 4 09:34:06 2005 Received: from fgwmail6.fujitsu.co.jp (fgwmail6.fujitsu.co.jp [192.51.44.36]) by server.ccl.net (8.12.8/8.12.8) with ESMTP id j04EY3k9007219 for ; Tue, 4 Jan 2005 09:34:04 -0500 Received: from m6.gw.fujitsu.co.jp ([10.0.50.76]) by fgwmail6.fujitsu.co.jp (8.12.10/Fujitsu Gateway) id j04EovqK006775 for ; Tue, 4 Jan 2005 23:50:57 +0900 (envelope-from m-ito_at_jp.fujitsu.com) Received: from s1.gw.fujitsu.co.jp by m6.gw.fujitsu.co.jp (8.12.10/Fujitsu Domain Master) id j04EovWa016746 for ; Tue, 4 Jan 2005 23:50:57 +0900 (envelope-from m-ito_at_jp.fujitsu.com) Received: from s1.gw.fujitsu.co.jp (s1 [127.0.0.1]) by s1.gw.fujitsu.co.jp (Postfix) with ESMTP id 0ADD437010A for ; Tue, 4 Jan 2005 23:50:57 +0900 (JST) Received: from dm.atsugi.flab.fujitsu.co.jp (dm.atsugi.flab.fujitsu.co.jp [10.36.64.1]) by s1.gw.fujitsu.co.jp (Postfix) with ESMTP id 9C8BA37010D for ; Tue, 4 Jan 2005 23:50:56 +0900 (JST) Received: from dm.atsugi.flab.fujitsu.co.jp by dm.atsugi.flab.fujitsu.co.jp (8.9.3p2/3.7W-041117-Fujitsu Labs. Atsugi Domain Mail Master (NAVGW)) id XAA15030; Tue, 4 Jan 2005 23:50:56 +0900 (JST) Received: from amailserv.atsugi.flab.fujitsu.co.jp ([10.36.100.4]) by dm.atsugi.flab.fujitsu.co.jp (NAVGW 2.5.2.9) with SMTP id M2005010423505526805 ; Tue, 04 Jan 2005 23:50:55 +0900 Received: from localhost (biobio2.cos.flab.fujitsu.co.jp [10.36.127.103]) by amailserv.atsugi.flab.fujitsu.co.jp (8.11.6+Sun/8.11.6) with ESMTP id j04Eos120936; Tue, 4 Jan 2005 23:50:54 +0900 (JST) Date: Tue, 04 Jan 2005 23:48:19 +0900 (JST) Message-Id: <20050104.234819.653215943.Masakatsu Ito_at_atsugi.flab.fujitsu.co.jp> To: chemistry_at_ccl.net Cc: m-ito_at_jp.fujitsu.com Subject: Ionizable residues affect the free energy calc.? From: Masakatsu Ito X-Mailer: Mew version 2.3 on XEmacs 21.1.14 (Cuyahoga Valley) Mime-Version: 1.0 Content-Type: Text/Plain; charset=us-ascii Content-Transfer-Encoding: 7bit X-Spam-Status: No, hits=4.0 required=7.5 tests=INVALID_MSGID,NO_RDNS2 autolearn=no version=2.61 X-Spam-Checker-Version: SpamAssassin 2.61 (1.212.2.1-2003-12-09-exp) on servernd.ccl.net Dear CCLers, I am wondering if an ionizable residue affects the accuracy of free energy calculation. We are trying to calculate the binding free energies of peptides to their receptor molecule using the 'double coupling' method (*) which requires two simulations. The first yields the free energy change, G1, for a transfer of a protonated peptide molecule, PH(+), from water to gas. PH(+)(aq) + Cl(-)(aq) -> PH(+):Cl(-)(gas) One chloride ion is added to neutralize the system. The second yields the free energy change, G2, for decoupling the peptide from the binding site of the solvated receptor, R(-)(aq) . R(-):PH(+)(aq) + Na(+)(aq) + Cl(-)(aq) -> R(-)(aq) + Na(+)(aq) + PH(+):Cl(-)(gas) Here a sodium ion is added to neutralize the system. The binding free energy is then G2 - G1 . But the problem is that the calculation would be more complicated if we consider all the charge configurations of the solvated peptide, PH(+)(aq) and P(aq). Because the protonated residue is arginine so far, I suppose the deprotonated configuration does not have to be considered. But this approximation is bad for lysine or histidine, and how can I estimate the error? Or how can I resolve the problem? I would be very grateful if you give me some advice or point me to articles dealing with similar problems. ( Please tell me if there is any paper estimating the binding affinities of ioniable ligands into a receptor. ) Thanks in advance for any help. Kind Regards, Masakatsu (*) M.K. Gilson et al. Biophys. J. 72, 1047 (1997) ; J. Herman and S, Shankler, Isr. J. Chem. 27,225 (1986) ; L. Zhang and J. Hermans, Proteins: Struct. Func. Gen. 24, 433 (1996); Roux et al. Biophys. J. 71, 670 (1996) -------------------------------------------------------------------- Masakatsu Ito Nanotechnology Research Center FUJITSU LABORATORIES LTD. 10-1 Morinosato-Wakamiya, Atsugi 243-0197 Japan Phone : +81-46-250-8234 Fax : +81-46-250-8844 E-mail m-ito_at_jp.fujitsu.com