RE: AMBER: Is the MD simulation normal

From: Yong Duan <>
Date: Thu, 26 May 2005 23:17:00 -0700

Dear Shulin,

Based on the detail you provided, I feel that the simulation actually
went ok. Break of two hydrogen bonds was a bit puzzling initially. Now,
it is clear that it was due to the weak affinity. The inhibitor moved a
little bit at the binding site. As a result, two of the hydrogen bonds
were lost that were replaced by two other H-bonds. "O4" was close to
both main chain carbonyl of Asn97 and Ile96 and can potentially form
H-bond with either (but not both). Same is true for O1.

7 uM level binding is pretty weak. I suspect that the B-factors of the
inhibitor could be high. If so, it implies what you observed is just
normal. Secondly, if things go well, you will eventually see reformation
of the initial H-bonds if you simulate the system for much longer time.
Of course, it is a matter of wild guess as to how much longer you still

-----Original Message-----
From: [] On Behalf
Of Shulin Zhuang
Sent: Thursday, May 26, 2005 9:24 PM
Subject: Re: AMBER: Is the MD simulation normal

Dear Prof. Duan and Prof. Cheatham,

Appreciated for your kind answer! According to your valuable advice, I
describe my MD in more detail.

To Prof. Cheatham:
>If you were using constant pressure with restraints (NTR=1), then the
relative >positions of the molecules may change due to pressure scaling.
To get around >this, only restrain the protein and add in explicit hbond
restraints (using the NMR >options) for the equilibration phase.

 I do not use constant pressure with restraints (NTR=1), but use
constant volume with restraints (NTR=1) to heat up the system.

For the MD details:
Several- stage constraints minimizations were performed first and then
50 ps NVT MD to heat up the system from 0 K to 300k was performed.
During the constraints, I just only let the hydrogen free and at the NVT
MD stage, the constraints force was 5 kcal/mol. After above, the
following 1 ns NPT MD without any constraints was carried out.

To Prof. Duan:
>1) How soon did you loss that hydrogen bond and did it ever go back.

One hydrogen bond lose after 200 ps and another new hydrogen bond forms;
after about 20 ps , another hydrogen bonds was lost and another new
hydrogen bond forms. In a word, two hydrogen bonds were lost and another
two hydrogen bonds forms at the same time stage. I have attached
several figures. Please examine the attached files. Take you time.

>2) Is the hydrogen bond exposed to solvent? This can give you clue as
the stability.
The two hydrogen bonds are not exposed to solvent.

>3) It sounds like that your complex is a bit unstable. Any experimental

>data on binding affinity (IC50 or Kd)?

The IC50 is 7 uM, therefore, the inhibitory has a weak binding affinity.

>Keep in mind, hydrogen bonds are weak interactions. Lossing one or two
>is quite common even for stable complex. Hydrogen bonds of 3A or so are

>not considered stable, if that is the distance your system started

Two hydrogen bond of my system start from a distance of 2.9 A, 3 A ,

best regards

   Shulin Zhuang
Chemistry Department 
Zhejiang University PRC
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Received on Fri May 27 2005 - 07:53:00 PDT
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