Clase 6: Detalles Clase 6: Detalles de la simulaciónde la simulación

SANDER

Estructura Parámetros

LEaP

NMR, X-Ray,... QM, crystal data, experiments,...

nucgen( Construcción de ác. nucléicos )

resp

( Ajuste de cargas electrostáticas )

coordinate_file topology_file

Antechamber( Set-up automatizado )

gibbssanderLES( Estrategia especial de aumento de sampling conformaciona en MD )

( Dinámica molecular) ( Cálculo de diferencias de energía libre )

ptraj carnal anal MM-PBSA

Programas de análisis

( Procesado de trayectorias ) ( Análisis de energías ) ( Cálculo de energías libres )

Obtención dedatos útiles en NMR

intense

spectrum

fantasian

profec

( Genera grids de reactividad basadas en energía libre )

nmode

( Análisis de modos normales )

Estructura Parámetros

LEaP

NMR, X-Ray,... QM, crystal data, experiments,...

coordinate_file topology_file

SANDER( Dinámica molecular)

ptraj carnal anal MM-PBSA

Programas de análisis

( Procesado de trayectorias ) ( Análisis de energías ) ( Cálculo de energías libres )

Descripción general Descripción general simulaciónsimulación

• TIMLIM: Tiempo límite CPU simulaciónTIMLIM: Tiempo límite CPU simulación

• IMIN: Decisión tipo cálculoIMIN: Decisión tipo cálculo– 0: 0: DinámicaDinámica– 1: Minimización1: Minimización

• NMROPT: Flag NMRNMROPT: Flag NMR– 0: 0: No NMR restrainsNo NMR restrains– >0: NMR restrains/weight changes>0: NMR restrains/weight changes– 2: NOESY volume restraints or chemical shifts 2: NOESY volume restraints or chemical shifts

restrainsrestrains

Nature & Format of the Nature & Format of the inputinput

• NTX: Read coordinates, velocities and box NTX: Read coordinates, velocities and box – 1: X formatted no V1: X formatted no V– 5: X and V are read formatted5: X and V are read formatted– 7: X,V and Box are read formatted7: X,V and Box are read formatted

• IREST: Flag to restart the run:IREST: Flag to restart the run:– 0 No0 No– 1 Restart (need X, V)1 Restart (need X, V)

• NTRX: Format for restraint from file refcNTRX: Format for restraint from file refc– 0 unformatted0 unformatted– 1 formatted1 formatted

Nature & Format of the Nature & Format of the outputoutput

• NTX0: Format for coordinates velocities NTX0: Format for coordinates velocities and boxand box– 1: X formatted 1: X formatted – 0: unformatted0: unformatted

• NTPR: Every NTPR mdifo will be printed.NTPR: Every NTPR mdifo will be printed.

• NTWR: Every NTWR restart file will be NTWR: Every NTWR restart file will be written.written.

• IWRAP: 1 Center solute in the primary box.IWRAP: 1 Center solute in the primary box.

Nature & Format of the Nature & Format of the outputoutput

• NTWX, NTWV, NTWE: frequency of the output NTWX, NTWV, NTWE: frequency of the output of coordinates, velocities, energies (If .ne. 0)of coordinates, velocities, energies (If .ne. 0)

• NTWXM, NTWVM, NTWEM: If .ne. 0 limits the NTWXM, NTWVM, NTWEM: If .ne. 0 limits the output of coordinates, velocities, energiesoutput of coordinates, velocities, energies

• NTWPRT: archive limit flag (V,X)NTWPRT: archive limit flag (V,X)– 0 all atoms0 all atoms– <0 only solute<0 only solute– >0 only atoms 1>0 only atoms 1NTWPRTNTWPRT

Potential functionPotential function

• NTF Force evaluationNTF Force evaluation– 1: complete interaction1: complete interaction– 2: bonds involving H are omitted2: bonds involving H are omitted– 3: all the bonds are omitted3: all the bonds are omitted– ......

• NTB Periodic boundary conditionsNTB Periodic boundary conditions– 0: No periodicity0: No periodicity– 1: Constant volume1: Constant volume– 2: Constant pressure2: Constant pressure

Periodic Boundary Periodic Boundary ConditionsConditions

(PBC)(PBC)

Potential functionPotential function

• DIELC: multiplicative factor for DIELC: multiplicative factor for dielectric constant default dielectric constant default 1.0. 1.0. See See options in GB/SAoptions in GB/SA

• CUT: Cutoff for non-bonded CUT: Cutoff for non-bonded interactions. interactions. See EwaldSee Ewald

• SCNB: Scaling of 1-4 vW interactions SCNB: Scaling of 1-4 vW interactions (1/SCNB). (1/SCNB). Default 2Default 2

• SCEE: Scaling of 1-4 electrostatic SCEE: Scaling of 1-4 electrostatic (1/SCEE). (1/SCEE). Default 1.2Default 1.2

Potential functionPotential functionGB calculationsGB calculations

• IGB: Use of generalized Born model (GB) IGB: Use of generalized Born model (GB) IGB=0 no IGB=0 no GBGB, IGB=1. (GB/SA), IGB=2 (vacuum calculation), , IGB=1. (GB/SA), IGB=2 (vacuum calculation), IGB=3 (dist. dep. dielc const.)IGB=3 (dist. dep. dielc const.)

• GBPARM: 1 (Beveridge), 2 (Case) Two sets of GB GBPARM: 1 (Beveridge), 2 (Case) Two sets of GB parametersparameters

• READRAD: if .ne.0 read vW radii for GB READRAD: if .ne.0 read vW radii for GB calculationscalculations

• OFFSET: fine tune of Born radii defaults 0.09 or 0OFFSET: fine tune of Born radii defaults 0.09 or 0• IGBFREQ: Frequency of update of Born radiiIGBFREQ: Frequency of update of Born radii• GBSA: If .eq.1 SA corrections to GB.GBSA: If .eq.1 SA corrections to GB.• SURFTEN: Use non-default surface tension.SURFTEN: Use non-default surface tension.

Generalized BornGeneralized Born

Método de introducir solvente continuo

elestersol GGG kk

kster SASG

nm GB

jiele

QQG

,

11

2

1

)exp(2ijjiijGB DR

ji

ijij d

RD

2

Técnica potente pero poco contrastada

No recomendada para no expertos

Potential functionPotential functionPolarizable potentialsPolarizable potentials

• IPOL. Inclusion of polarizationIPOL. Inclusion of polarization– 0 No polarization0 No polarization– 1 Use polarization1 Use polarization– 2 Use polarization + 3 body interactions2 Use polarization + 3 body interactions

No recomendado para no expertos

Potential functionPotential functionFrozen/restrained atomsFrozen/restrained atoms

• IBELLY:IBELLY:– 0 normal run0 normal run– 1 Belly run. Only a set of atoms 1 Belly run. Only a set of atoms

(specified later) are allowed to move(specified later) are allowed to move

• NTR: Restraints in the Cartesian NTR: Restraints in the Cartesian space (use harmonic restraints)space (use harmonic restraints)– 0 No restraints0 No restraints– 1 MD with restraints on specific atoms1 MD with restraints on specific atoms

Energy minimizationEnergy minimization

• MAXCYC: Maximum number of cycles.MAXCYC: Maximum number of cycles.• NCYC: After NCYC change from one NCYC: After NCYC change from one

method of optimization to other.method of optimization to other.• NTMIN: Method for minimizationNTMIN: Method for minimization

– 0 Conjugate gradient0 Conjugate gradient– 1 For NCYC steepest descent then CG1 For NCYC steepest descent then CG– 2 Only steepest descent2 Only steepest descent

• DX0, DXM, DRMS: Details of minimization DX0, DXM, DRMS: Details of minimization procedure: Use defaultsprocedure: Use defaults

Molecular dynamicsMolecular dynamics

• NSTLIM: Number of MD-steps per NRUN to be NSTLIM: Number of MD-steps per NRUN to be performedperformed

• NDFMIN: Number degrees of freedom to remove. If NDFMIN: Number degrees of freedom to remove. If NTCM or NSCM.ne.0 use 6, otherwise 0.NTCM or NSCM.ne.0 use 6, otherwise 0.

• NTCM:NTCM:– 0 Do not remove translational/rotational moves around center 0 Do not remove translational/rotational moves around center

of massof mass– 1 Remove at the beginning1 Remove at the beginning

• NSCM: Remove translational/rotational moves around NSCM: Remove translational/rotational moves around center of mass every NSCN steps center of mass every NSCN steps (def 0)(def 0)

• T: Time at the start, T: Time at the start, default 0.0default 0.0• DT: Integration timeDT: Integration time

Etapa de integraciónEtapa de integración

• Si no constraints en ningún enlace 0.0005 ps.Si no constraints en ningún enlace 0.0005 ps.

• Si constraints (SHAKE) en enlaces X-H 0.001 psSi constraints (SHAKE) en enlaces X-H 0.001 ps

• Si constraints en todos los enlaces 0.002Si constraints en todos los enlaces 0.002

• Si el sistema esta muy tensionado, T o P es Si el sistema esta muy tensionado, T o P es elevada usar 0.001 pselevada usar 0.001 ps

• Reducir la etapa de integración aumenta Reducir la etapa de integración aumenta linealmente el costo de la simulación pero linealmente el costo de la simulación pero puede ser necesario para evitar puede ser necesario para evitar discontinuidadesdiscontinuidades

Regulación de la Regulación de la temperaturatemperatura• TEMP0: Reference temperatureTEMP0: Reference temperature

• TEMPI: Starting temperature. Flag important when TEMPI: Starting temperature. Flag important when random velocities are generated.random velocities are generated.

• IG: Seed random number for velocity calculationIG: Seed random number for velocity calculation• NTT: Temperature scalingNTT: Temperature scaling

– 0 Constant energy run. No scaling0 Constant energy run. No scaling– 1 Constant T. Use Berendsen’s coupling1 Constant T. Use Berendsen’s coupling– 4 When T deviates from TEMP0 more than DTEMP scale 4 When T deviates from TEMP0 more than DTEMP scale

velocities, otherwise do not scalevelocities, otherwise do not scale

• TAUTP: Time constant for heat bath coupling: Default TAUTP: Time constant for heat bath coupling: Default 1.0. Smaller value tighter coupling1.0. Smaller value tighter coupling

• VLIMIT: IF .ne.0 when velocity of one atom is >VLIMIT set VLIMIT: IF .ne.0 when velocity of one atom is >VLIMIT set velocity=VLIMITvelocity=VLIMIT

Regulación de la presiónRegulación de la presión(NTB=2)(NTB=2)

• NTP: Flag for constant pressure dynamicsNTP: Flag for constant pressure dynamics– 0 no constant pressure0 no constant pressure– 1 MD isotropic scaling1 MD isotropic scaling– 2 MD anisotropic scaling2 MD anisotropic scaling

• PRES0: Pressure PRES0: Pressure (1 atm default).(1 atm default).• COMP: Compressibility of the system. COMP: Compressibility of the system. In general In general

use water value (44.6)use water value (44.6)• TAUP: Pressure relaxation time TAUP: Pressure relaxation time (0.2 ps)(0.2 ps)• NPSCAL: Modelo de escalado posicionesNPSCAL: Modelo de escalado posiciones

– 0: atom scaling: can compress bonds.0: atom scaling: can compress bonds.– 1: Molecule scaling1: Molecule scaling

SHAKESHAKE

• NTC: Flag to use SHAKE (In general a NTC: Flag to use SHAKE (In general a good idea for normal systems)good idea for normal systems)– 1 Do not use SHAKE1 Do not use SHAKE– 2 SHAKE on X-H bonds2 SHAKE on X-H bonds– 3 SHAKE on all the bonds3 SHAKE on all the bonds

• TOL: Tolerance for coordinate TOL: Tolerance for coordinate resetting in SHAKE. Default 0.0005 Å.resetting in SHAKE. Default 0.0005 Å.

WATER CAPWATER CAP(gota de agua)(gota de agua)

• IVCAP:IVCAP:– 0 in effect if defined in parm0 in effect if defined in parm– 1 Cap in effect, but pointer will be 1 Cap in effect, but pointer will be

modified (MATCAP)modified (MATCAP)– 2 Cap will be inactivated2 Cap will be inactivated

• FCAP:FCAP:– Force constant for Cap (half harmonic). Force constant for Cap (half harmonic).

Default 1.5 kcal/mol ÅDefault 1.5 kcal/mol Å22

PARTICLE MESH EWALDPARTICLE MESH EWALD

• Es una técnica muy poderosa para incluir Es una técnica muy poderosa para incluir interacciones electrostática de largo alcance.interacciones electrostática de largo alcance.

• Es totalmente necesaria para simular DNAEs totalmente necesaria para simular DNA

• Recomendable para proteínas, sobre todo si Recomendable para proteínas, sobre todo si están muy cargadasestán muy cargadas

• Sobreestima la periodicidad de la simulación.Sobreestima la periodicidad de la simulación.

• Últimas versiones de AMBER lo toman como Últimas versiones de AMBER lo toman como defecto de la simulación.defecto de la simulación.

PARTICLE MESH EWALDPARTICLE MESH EWALD

• &ewald namelist&ewald namelist– A,B,C. The PME unit cellA,B,C. The PME unit cell– Alpha,Beta,GAMMA: Cell anglesAlpha,Beta,GAMMA: Cell angles– NFFT1,NFFT2,NFFT3: Size of charge grid. NFFT1,NFFT2,NFFT3: Size of charge grid.

In general choose =A,B,C i.e grid In general choose =A,B,C i.e grid spacing 1 Åspacing 1 Å

– Use defaults for all the other parametersUse defaults for all the other parameters

NMR REFINEMENTNMR REFINEMENT

• La mayoría de usuarios usa MD solo para La mayoría de usuarios usa MD solo para refinar la geometría a partir de las refinar la geometría a partir de las restricciones de distancias o ángulos restricciones de distancias o ángulos derivadas a partir de otros programas DIANA, derivadas a partir de otros programas DIANA, MARDIGRAS,...MARDIGRAS,...

• Estas restricciones se introducen como “flat Estas restricciones se introducen como “flat harmonic restraints” que se añaden al force-harmonic restraints” que se añaden al force-field.field.

• Es posible introducir otras restricciones más Es posible introducir otras restricciones más elaboradas: Time averaged restrains, noesy elaboradas: Time averaged restrains, noesy volumes, dipolar couplings,...volumes, dipolar couplings,...

NMR REFINEMENTNMR REFINEMENT

• ISCALE: Number of additional variables to ISCALE: Number of additional variables to optimize (in addition to 3N coordinates)optimize (in addition to 3N coordinates)

• NOESKP: How often are the NOESY volumes NOESKP: How often are the NOESY volumes computedcomputed

• IPNLTY: IPNLTY: – 1 minimize the abs value of errors (R-factor)1 minimize the abs value of errors (R-factor)– 2 minimize the RMS (sum square errors)2 minimize the RMS (sum square errors)– 3 Special treatment for NOESY intensities 3 Special treatment for NOESY intensities

• MXSUB: Number of submolecules to be use MXSUB: Number of submolecules to be use def 1def 1

Restraints fileRestraints file

• IRESID (restraints definition)IRESID (restraints definition)– 0 global atom numbers0 global atom numbers– 1 global residue number1 global residue number

• IAT(1)IAT(1)IAT(4) if IRESID=0 atoms to restraints IAT(4) if IRESID=0 atoms to restraints (IAT(3)=0, distance, IAT(4)=0 angle, otherwise (IAT(3)=0, distance, IAT(4)=0 angle, otherwise torsion). If IRESID=1 residue number, then torsion). If IRESID=1 residue number, then ATNAM(1)ATNAM(1)ATNAM(2) define the atom #s.ATNAM(2) define the atom #s.

• NSTEP1, NSTEP2 use restraints only between NSTEP1, NSTEP2 use restraints only between these two integration steps. these two integration steps. Def uses always 0Def uses always 0

• IRSTYP: IRSTYP: Absolute (0)Absolute (0) or relative (1) restraints or relative (1) restraints

Restraints fileRestraints file

• IALTD: Ignore large violation if 1. If 0 IALTD: Ignore large violation if 1. If 0 (default) not ignore(default) not ignore

• IFVARI: Change force or target value IFVARI: Change force or target value along the trajectory (R1Aalong the trajectory (R1AR4A, R4A, RK2ARK2ARK3A.RK3A.

• NINC, IMULT: Define how the NINC, IMULT: Define how the target/force values change along the target/force values change along the trajectory trajectory (use defaults).(use defaults).

Restraints fileRestraints file

• La forma del restraints es un pozo plano La forma del restraints es un pozo plano (si IALTD=0, default)(si IALTD=0, default)– R1R1R4; RK2R4; RK2RK3; R1ARK3; R1AR4A; RK2R4A; RK2RK3RK3

• Si R (valor en la simulación)Si R (valor en la simulación)– R<r1 o R>4. Liniar slope restraintR<r1 o R>4. Liniar slope restraint– R2<R<R3 E=0 (flat)R2<R<R3 E=0 (flat)– Parabolic constraint otherwiseParabolic constraint otherwise

• La forma del restraints varia para IALTD=1La forma del restraints varia para IALTD=1

Restraints fileRestraints file

• IGR1(i),i=1IGR1(i),i=1200. IGR2(i), =1200. IGR2(i), =1200. 200. Se usan para definir restraints sobre Se usan para definir restraints sobre un grupo de átomos. Se calculan un grupo de átomos. Se calculan promedio de posiciones con esas promedio de posiciones con esas listaslistas

Other restraints Other restraints (used for NMR refinement)(used for NMR refinement)

• Es posible incluir restraints Es posible incluir restraints adicionalesadicionales– NOESY volume restraintsNOESY volume restraints– Chemical shifts restraintsChemical shifts restraints– Direct dipolar coupling restraintsDirect dipolar coupling restraints– Restraints de quiralidadRestraints de quiralidad– Time-averaged constraintsTime-averaged constraints

• Se puede activar opción LES Se puede activar opción LES (multiple-copies)(multiple-copies)