AMBER Archive (2006)

Subject: Re: AMBER: Simulating proteins with calcium ion

From: Qing Zhang (qingzhang_nyu_at_yahoo.com)
Date: Fri Dec 08 2006 - 18:31:02 CST

Thanks for the replies of Fenghui and Tom. I did further analysis including energy decompositions, and its points to the van der Waals parameters for Ca2+ in parm99.dat. I am giving a more detailed description of the system/problem and my analysis. The description will automatically answer some questions by Fenghui and Tom, and I will explicitly anwer the rest.

The system:
A protein-protein complex with a structural Ca2+. The Ca2+ ion binds to 6 oxygens from 5 residues (2 GLN, 2 ASP, and 1 GLY). The 6 oxygens form a binding pocket like a half-sphere, and Ca2+ is located nearly at the sphere center. The distances between the oxygens and Ca2+ range from 2.2 to 2.5 Angstrom.

The problem:
Energy minimizations of the complex crystal structure (using AMBER 9) cause Ca2+ to escape the half-sphere by about 1.9 Angstrom to the solvent but still binds to a few oxygens (Tom, there is no move/penetration through other atoms). I used 400 SD followed by 600 CG with igb=5 and a 3 kcal/mol (or 10) restraint on the heavy atoms of the proteins and Ca2+. Crystal waters are built into the system but there is no explicit sovlent. A sample input file is below.
--------------------------------------------------------
Minimization with Cartesian restraints
 &cntrl
    imin=1, maxcyc=1000, ntmin=1, ncyc=400,
    scee=1.2,
    igb=5,
    ntb=0, cut=16.0,
    ntpr=100,
    ntr=1, restraint_wt=3.0, restraintmask=':1-297 & !@H=',
    ntc=2,
 /
--------------------------------------------------------

The analysis:
The first thing came to my mind is the radius of Ca2+ in parm99.dat. As the 6 oxygens (type O2 and O) have radii of 1.6612 (parm99.dat) and the distances between Ca2+ and the oxygens range from 2.2 to 2.5, the large raius for Ca2+ in parm99.dat (1.7131) will cause a large van der Waals penalty and make Ca2+ to be pushed out of the binding pocket. So I did energy composition analysis on Ca2+ (idecomp=2 and the restraint is removed to make idecomp work). The initial structure with only 1 SD gives a vdw of
nal |vdw |eel |pol |sas
        290 0.000 49.029 -353.216 32.657 0.000

Minimization with 400 SD (no CG as Tom suggested it might cause large jumps) leads to the same dislocation of Ca2+ and gives a vdw of 6 and eel of -350:
        resid |internal |vdw |eel |pol |sas
        290 0.000 5.994 -350.108 19.389 0.000

It indicates that Ca2+ is pushed out of the binding pocket during minimization to reduce van der Waals penalty.

In order to further prove it, I reduced the radius of Ca2+ to about 1.3. This is based on a post by Kenley Barrett on AMBER achieve. In this post, the vdw parameters for divalent ions computed based on the Aqvist paper (JPC 1990,k 94: 8021) are listed:
http://amber.ch.ic.ac.uk/archive/200504/0376.html

I took the vdw parameters of Ca2+ (1.3263, 0.4497) from the post, replaced those (for C0) in parm99.dat, and re-generated the topology file. The energy decompostion on the initial structure with 1 SD show a vdw of only 6 (reduced from 49):
        resid |internal |vdw |eel |pol |sas
        290 0.000 6.452 -353.216 32.657 0.000

Then I minimized the system for 400 SD (same minimization condition as the run without radius modification). The Ca2+ ion stays at its crystal location! The movement is only 0.13 Angstrom, and the energy decomposition shows a vdw of 12 and eel of -396:
        resid |internal |vdw |eel |pol |sas
        290 0.000 11.906 -395.934 61.374 0.000

>From these observations, the instability of Ca2+ during the minimizations is clearly due to the vdw parameters for Ca2+ in parm99.dat.

I am not familiar with divalent vdw parameterization. If someone has more insights on this, please feel free to raise them.

Thanks,

Qing
======================================
Qing Zhang, Ph.D.
Research Associate
Department of Molecular Biology, MB-5
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, CA 92037-1000
Tel: (858) 784-2333
Fax: (858) 784-2860
ebsite: http://www.qingzhang.info
======================================

 
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