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本帖最后由 killua1 于 2023-6-12 23:41 编辑
接触gromacs不久，有些困惑麻烦老师解答，谢谢！
目的：想通过gromacs模拟一个蛋白和水的体系在低温下（255 K）随时间延长，蛋白发生的变化
背景1：mdp文件来源，“水中的溶菌酶教程”。所用gromacs版本是sob老师编译的windows 2020.6_gpu加速版。然后将nvt.mdp npt.mdp md.mdp的ref_t部分改成了255 K，开始模拟。根据模拟过程中相应的notes和warning对mdp进行了修改，主要包括1.将ions.mdp中的coulombtype = cutoff改成PME，2.将npt.mdp中pcoupl= Parrinello-Rahman改成Berendsen。开始模拟。
背景2：根据背景1的模拟结果发现在经过100 ns的模拟后，RMSD仍呈上升趋势，如下图所示，所以觉得是不是mdp的参数不合理
背景3：最近通过学习了解到一些新知识，于是又对mdp进行了修改，主要包括：1.将minim.mdp中加一行define = -DFLEXIBLE使用柔性水，参考帖子：http://bbs.keinsci.com/thread-12013-1-1.html；2.将nvt.mdp中的ref_t改回300 K，将gen-temp = 300 改成50，参考帖子：http://bbs.keinsci.com/thread-20482-1-1.html；3.将npt.mdp中define = -DPORSES用;注释掉，添加退火参数，从300 K逐渐降至255 K，目的是先让蛋白充分弛豫在逐渐降温至目的温度，参考帖子：http://bbs.keinsci.com/thread-20213-1-1.html。然后进行最后的模拟，具体mdp参数如下。
（1）ions.mdp文件的内容：
; ions.mdp - used as input into grompp to generate ions.tpr
; Parameters describing what to do, when to stop and what to save
integrator = steep ; Algorithm (steep = steepest descent minimization)
emtol = 1000.0 ; Stop minimization when the maximum force < 1000.0 kJ/mol/nm
emstep = 0.01 ; Minimization step size
nsteps = 50000 ; Maximum number of (minimization) steps to perform
; Parameters describing how to find the neighbors of each atom and how to calculate the interactions
nstlist = 1 ; Frequency to update the neighbor list and long range forces
cutoff-scheme = Verlet ; Buffered neighbor searching
ns_type = grid ; Method to determine neighbor list (simple, grid)
coulombtype = PME ; Treatment of long range electrostatic interactions
rcoulomb = 1.0 ; Short-range electrostatic cut-off
rvdw = 1.0 ; Short-range Van der Waals cut-off
pbc = xyz ; Periodic Boundary Conditions in all 3 dimensions
（2）minim.mdp文件的内容：
; minim.mdp - used as input into grompp to generate em.tpr
; Parameters describing what to do, when to stop and what to save
define = -DFLEXIBLE ; 能量最小化时使用柔性水
integrator = steep ; Algorithm (steep = steepest descent minimization)
emtol = 1000.0 ; Stop minimization when the maximum force < 1000.0 kJ/mol/nm
emstep = 0.01 ; Minimization step size
nsteps = 50000 ; Maximum number of (minimization) steps to perform
; Parameters describing how to find the neighbors of each atom and how to calculate the interactions
nstlist = 1 ; Frequency to update the neighbor list and long range forces
cutoff-scheme = Verlet ; Buffered neighbor searching
ns_type = grid ; Method to determine neighbor list (simple, grid)
coulombtype = PME ; Treatment of long range electrostatic interactions
rcoulomb = 1.0 ; Short-range electrostatic cut-off
rvdw = 1.0 ; Short-range Van der Waals cut-off
pbc = xyz ; Periodic Boundary Conditions in all 3 dimensions
（3）nvt.mdp文件的内容：
title = OPLS Lysozyme NVT equilibration
define = -DPOSRES ; position restrain the protein
; Run parameters
integrator = md ; leap-frog integrator
nsteps = 100000 ; 2 * 100000 = 200 ps
dt = 0.002 ; 2 fs
; Output control
nstxout = 500 ; save coordinates every 1.0 ps
nstvout = 500 ; save velocities every 1.0 ps
nstenergy = 500 ; save energies every 1.0 ps
nstlog = 500 ; update log file every 1.0 ps
; Bond parameters
continuation = no ; first dynamics run
constraint_algorithm = lincs ; holonomic constraints
constraints = h-bonds ; bonds involving H are constrained
lincs_iter = 1 ; accuracy of LINCS
lincs_order = 4 ; also related to accuracy
; Nonbonded settings
cutoff-scheme = Verlet ; Buffered neighbor searching
ns_type = grid ; search neighboring grid cells
nstlist = 10 ; 20 fs, largely irrelevant with Verlet
rcoulomb = 1.0 ; short-range electrostatic cutoff (in nm)
rvdw = 1.0 ; short-range van der Waals cutoff (in nm)
DispCorr = EnerPres ; account for cut-off vdW scheme
; Electrostatics
coulombtype = PME ; Particle Mesh Ewald for long-range electrostatics
pme_order = 4 ; cubic interpolation
fourierspacing = 0.16 ; grid spacing for FFT
; Temperature coupling is on
tcoupl = V-rescale ; modified Berendsen thermostat
tc-grps = Protein Non-Protein ; two coupling groups - more accurate
tau_t = 0.1 0.1 ; time constant, in ps
ref_t = 300 300 ; reference temperature, one for each group, in K 在较高温度下进行弛豫
; Pressure coupling is off
pcoupl = no ; no pressure coupling in NVT
; Periodic boundary conditions
pbc = xyz ; 3-D PBC
; Velocity generation
gen_vel = yes ; assign velocities from Maxwell distribution
gen_temp = 50 ; temperature for Maxwell distribution 按照讲义建议，小一些，默认300
gen_seed = -1 ; generate a random seed
（4）npt.mdp文件的内容：
title = OPLS Lysozyme NPT equilibration
; define = -DPOSRES ; position restrain the protein不要限制蛋白势，进行退火弛豫
; Run parameters
integrator = md ; leap-frog integrator
nsteps = 500000 ; 2 * 500000 = 1 ns
dt = 0.002 ; 2 fs
; Output control
nstxout = 500 ; save coordinates every 1.0 ps
nstvout = 500 ; save velocities every 1.0 ps
nstenergy = 500 ; save energies every 1.0 ps
nstlog = 500 ; update log file every 1.0 ps
; Bond parameters
continuation = yes ; Restarting after NVT
constraint_algorithm = lincs ; holonomic constraints
constraints = h-bonds ; bonds involving H are constrained
lincs_iter = 1 ; accuracy of LINCS
lincs_order = 4 ; also related to accuracy
; Nonbonded settings
cutoff-scheme = Verlet ; Buffered neighbor searching
ns_type = grid ; search neighboring grid cells
nstlist = 10 ; 20 fs, largely irrelevant with Verlet scheme
rcoulomb = 1.0 ; short-range electrostatic cutoff (in nm)
rvdw = 1.0 ; short-range van der Waals cutoff (in nm)
DispCorr = EnerPres ; account for cut-off vdW scheme
; Electrostatics
coulombtype = PME ; Particle Mesh Ewald for long-range electrostatics
pme_order = 4 ; cubic interpolation
fourierspacing = 0.16 ; grid spacing for FFT
; Temperature coupling is on
tcoupl = V-rescale ; modified Berendsen thermostat
tc-grps = Protein Non-Protein ; two coupling groups - more accurate
tau_t = 0.1 0.1 ; time constant, in ps
ref_t = 255 255 ; reference temperature, one for each group, in K
; Annealing simulation 进行退火
annealing = single single ;Type of annealing
annealing_npoints = 6 6 ;Number of annealing points
annealing_time = 0 160 320 480 640 800 0 160 320 480 640 800 ;Time to reach the target
annealing_temp = 300 290 280 270 260 255 300 290 280 270 260 255 ;Initial and final temperature
; Pressure coupling is on
pcoupl = Berendsen ; Pressure coupling on in NPT
pcoupltype = isotropic ; uniform scaling of box vectors
tau_p = 2.0 ; time constant, in ps
ref_p = 1.0 ; reference pressure, in bar
compressibility = 4.5e-5 ; isothermal compressibility of water, bar^-1
refcoord_scaling = com
; Periodic boundary conditions
pbc = xyz ; 3-D PBC
; Velocity generation
gen_vel = no ; Velocity generation is off
（5）md.mdp文件的内容：
title = OPLS Lysozyme NPT equilibration
; Run parameters
integrator = md ; leap-frog integrator
nsteps = 50000000 ; 2 * 50000000 = 100000 ps (100 ns)
dt = 0.002 ; 2 fs
; Output control
nstxout = 0 ; suppress bulky .trr file by specifying
nstvout = 0 ; 0 for output frequency of nstxout,
nstfout = 0 ; nstvout, and nstfout
nstenergy = 5000 ; save energies every 10.0 ps
nstlog = 5000 ; update log file every 10.0 ps
nstxout-compressed = 5000 ; save compressed coordinates every 10.0 ps
compressed-x-grps = System ; save the whole system
; Bond parameters
continuation = yes ; Restarting after NPT
constraint_algorithm = lincs ; holonomic constraints
constraints = h-bonds ; bonds involving H are constrained
lincs_iter = 1 ; accuracy of LINCS
lincs_order = 4 ; also related to accuracy
; Neighborsearching
cutoff-scheme = Verlet ; Buffered neighbor searching
ns_type = grid ; search neighboring grid cells
nstlist = 10 ; 20 fs, largely irrelevant with Verlet scheme
rcoulomb = 1.0 ; short-range electrostatic cutoff (in nm)
rvdw = 1.0 ; short-range van der Waals cutoff (in nm)
; Electrostatics
coulombtype = PME ; Particle Mesh Ewald for long-range electrostatics
pme_order = 4 ; cubic interpolation
fourierspacing = 0.16 ; grid spacing for FFT
; Temperature coupling is on
tcoupl = V-rescale ; modified Berendsen thermostat
tc-grps = Protein Non-Protein ; two coupling groups - more accurate
tau_t = 0.1 0.1 ; time constant, in ps
ref_t = 255 255 ; reference temperature, one for each group, in K
; Pressure coupling is on
pcoupl = Parrinello-Rahman ; Pressure coupling on in NPT
pcoupltype = isotropic ; uniform scaling of box vectors
tau_p = 2.0 ; time constant, in ps
ref_p = 1.0 ; reference pressure, in bar
compressibility = 4.5e-5 ; isothermal compressibility of water, bar^-1
; Periodic boundary conditions
pbc = xyz ; 3-D PBC
; Dispersion correction
DispCorr = EnerPres ; account for cut-off vdW scheme
; Velocity generation
gen_vel = no ; Velocity generation is off
主要问题：
1.针对我的目的，这样的模拟思路合理吗？
2.目前的退火参数设置合理吗？NVT在高温下的时间是否太短了，目前是200 ps；另外关于NVT中的define = -DPOSRES ; position restrain the protein 是否应该注释掉，因为在不同的帖子中看到，有的说法如下图所示
；也有的说
；所以有些困惑，该不该限制
3.NPT中的参数设置是否合理？目前一共是1 ns
4.既然在NPT中为了退火将define = -DPOSRES注释掉了，那控压方式使用Berendsen或Parrinello-Rahman 还有什么区别吗？
5.从RMSD来看，100 ns仍未平衡，是否应该把NVT中的ref_t提到更高的温度，如400 K？
6.最后就是麻烦老师看下整体的mdp参数设置合理吗？
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发表于 Post on 2023-6-12 14:40:12
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楼主 Author
发表于 Post on 2023-6-13 14:02:52