Online citations, reference lists, and bibliographies.
Please confirm you are human
(Sign Up for free to never see this)
← Back to Search

A Point‐charge Force Field For Molecular Mechanics Simulations Of Proteins Based On Condensed‐phase Quantum Mechanical Calculations

Y. Duan, C. Wu, Shibasish Chowdhury, M. C. Lee, Guoming Xiong, Wei Zhang, Rong Yang, P. Cieplak, R. Luo, Taisung Lee, J. Caldwell, J. Wang, P. Kollman
Published 2003 · Physics, Medicine, Computer Science

Save to my Library
Download PDF
Analyze on Scholarcy
Share
Molecular mechanics models have been applied extensively to study the dynamics of proteins and nucleic acids. Here we report the development of a third‐generation point‐charge all‐atom force field for proteins. Following the earlier approach of Cornell et al., the charge set was obtained by fitting to the electrostatic potentials of dipeptides calculated using B3LYP/cc‐pVTZ//HF/6‐31G** quantum mechanical methods. The main‐chain torsion parameters were obtained by fitting to the energy profiles of Ace‐Ala‐Nme and Ace‐Gly‐Nme di‐peptides calculated using MP2/cc‐pVTZ//HF/6‐31G** quantum mechanical methods. All other parameters were taken from the existing AMBER data base. The major departure from previous force fields is that all quantum mechanical calculations were done in the condensed phase with continuum solvent models and an effective dielectric constant of ε = 4. We anticipate that this force field parameter set will address certain critical short comings of previous force fields in condensed‐phase simulations of proteins. Initial tests on peptides demonstrated a high‐degree of similarity between the calculated and the statistically measured Ramanchandran maps for both Ace‐Gly‐Nme and Ace‐Ala‐Nme di‐peptides. Some highlights of our results include (1) well‐preserved balance between the extended and helical region distributions, and (2) favorable type‐II poly‐proline helical region in agreement with recent experiments. Backward compatibility between the new and Cornell et al. charge sets, as judged by overall agreement between dipole moments, allows a smooth transition to the new force field in the area of ligand‐binding calculations. Test simulations on a large set of proteins are also discussed. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 1999–2012, 2003
This paper references
J Mol Biol
Y Duan (1997)
10.1126/SCIENCE.3576184
Free energy calculations by computer simulation.
P. Bash (1987)
J Phys Chem
C I Bayly (1993)
J Am Chem Soc
W D Cornell (1995)
10.1021/JA9939385
Molecular Dynamics Simulations of Nucleic Acids with a Generalized Born Solvation Model
Vickie Tsui and (2000)
J Chem Phys
A Klamt (1996)
10.1021/JA9621760
Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids
W. Jorgensen (1996)
Proc Natl Acad Sci
D Kihara (2001)
Chem Phys Lett
B Miehlich (200)
10.1016/S0301-4622(96)02238-7
Experimental measurement of the effective dielectric in the hydrophobic core of a protein.
B. García-Moreno (1997)
J Mol Biol
B Park (1996)
Proc Natl Acad Sci
Y Duan (1998)
J. A. Gaussian
M J Frisch (2001)
J Phys Chem
S C Harvey (1972)
10.1021/JP003919D
Evaluation and Reparametrization of the OPLS-AA Force Field for Proteins via Comparison with Accurate Quantum Chemical Calculations on Peptides†
George A. Kaminski and (2001)
10.1021/JA00124A002
A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules
Wendy D. Cornell (1995)
10.1146/ANNUREV.PHYSCHEM.51.1.129
Generalized born models of macromolecular solvation effects.
D. Bashford (2000)
10.1023/A:1007907925007
Adventures in Improving the Scaling and Accuracy of a Parallel Molecular Dynamics Program
M. Crowley (2004)
J Chem Phys
J Andzelm (1995)
Escom: The Netherlands
P A Kollman (1997)
J Chem Phys
E Cances (1997)
J Mol Biol
B Zagrovic (2001)
J Chem Phys
A D Becke (1993)
10.1126/SCIENCE.282.5389.740
Pathways to a protein folding intermediate observed in a 1-microsecond simulation in aqueous solution.
Y. Duan (1998)
10.1002/prot.1087
A distance‐dependent atomic knowledge‐based potential for improved protein structure selection
H. Lu (2001)
10.1002/prot.10286
Structure validation by Cα geometry: ϕ,ψ and Cβ deviation
S. Lovell (2003)
10.1002/(SICI)1097-0134(199705)28:1<59::AID-PROT6>3.0.CO;2-E
Curious structure in “canonical” alanine‐based peptides
W. Shirley (1997)
10.1002/jcc.10125
Development of a polarizable force field for proteins via ab initio quantum chemistry: First generation model and gas phase tests
George A. Kaminski (2002)
J Chem Soc Perkin Trans
A Klamt (1993)
10.1007/S002140000239
An improved iterative solution to solve the electrostatic problem in the polarizable continuum model
C. Pomelli (2001)
Proc Natl Acad Sci
C L Simmerling (1995)
10.1006/JMBI.1996.0256
Energy functions that discriminate X-ray and near native folds from well-constructed decoys.
B. Park (1996)
J Am Chem Soc
C D Snow (2002)
J Phys Chem B
P Ferrara (2000)
10.1002/prot.10279
Comparison of a QM/MM force field and molecular mechanics force fields in simulations of alanine and glycine “dipeptides” (Ace‐Ala‐Nme and Ace‐Gly‐Nme) in water in relation to the problem of modeling the unfolded peptide backbone in solution
H. Hu (2003)
10.1063/1.464913
Density-functional thermochemistry. III. The role of exact exchange
Axel D. Becke (1993)
Proc Natl Acad Sci
Z S Shi (2002)
10.1073/pnas.112193999
Polyproline II structure in a sequence of seven alanine residues
Z. Shi (2002)
10.1110/ps.0240103
The role of α‐, 310‐, and π‐helix in helix→coil transitions
R. Armen (2003)
10.1006/JMBI.2001.5033
β-hairpin folding simulations in atomistic detail using an implicit solvent model1
B. Zagrovic (2001)
J Chem Phys
W L Jorgensen (1983)
10.1021/J100665A011
Dielectric relaxation spectra of water adsorbed on lysozyme.
S. Harvey (1972)
10.1006/JMBI.1997.1247
Molecular dynamics simulation study of DNA dodecamer d(CGCGAATTCGCG) in solution: conformation and hydration.
Y. Duan (1997)
10.1021/JA962310G
Accurate ab Initio Quantum Chemical Determination of the Relative Energetics of Peptide Conformations and Assessment of Empirical Force Fields
M. Beachy (1997)
J Chem Phys
U Essmann (1995)
Biopolymers
S Chowdhury (2003)
10.1002/jcc.1079
Automatic parameterization of force field by systematic search and genetic algorithms
J. Wang (2001)
10.1063/1.462569
Electron affinities of the first‐row atoms revisited. Systematic basis sets and wave functions
Rick A. Kendall (1992)
10.1063/1.445869
Comparison of simple potential functions for simulating liquid water
W. Jorgensen (1983)
J Mol Biol
S Chowdhury (2003)
10.1063/1.470117
A smooth particle mesh Ewald method
U. Essmann (1995)
J Am Chem Soc
W L Jorgensen (1996)
J Am Chem Soc
M D Beachy (1997)
Phys Rev B
A F Voter (1998)
10.1021/JP027293Y
Force field influence on the observation of π-helical protein structures in molecular dynamics simulations
M. Feig (2003)
10.1002/jcc.10018
Identifying native‐like protein structures using physics‐based potentials
B. N. Dominy (2002)
10.1021/JA028604L
The Trp cage: folding kinetics and unfolded state topology via molecular dynamics simulations.
C. D. Snow (2002)
Biophys Chem
B Garciamoreno (1997)
Biophys J
J J Dwyer (1610)
10.1039/P29930000799
COSMO : a new approach to dielectric screening in solvents with explicit expressions for the screening energy and its gradient
A. Klamt (1993)
10.1021/JA9727023
COMBINED LOCALLY ENHANCED SAMPLING AND PARTICLE MESH EWALD AS A STRATEGY TO LOCATE THE EXPERIMENTAL STRUCTURE OF A NONHELICAL NUCLEIC ACID
C. Simmerling (1998)
10.1002/(SICI)1097-0134(199606)25:2<202::AID-PROT6>3.0.CO;2-J
Molecular dynamics simulations of synthetic peptide folding
S. S. Sung (1996)
10.1136/bmj.1.4959.155-a
Biochemistry
F. G. Young (1955)
10.1002/jcc.540070216
An all atom force field for simulations of proteins and nucleic acids
S. Weiner (1986)
J Chem Phys
R A Kendall (1992)
Phys Rev B
C Lee (1988)
10.1073/PNAS.95.17.9897
The early stage of folding of villin headpiece subdomain observed in a 200-nanosecond fully solvated molecular dynamics simulation.
Y. Duan (1998)
10.1016/0009-2614(89)87234-3
Results obtained with the correlation energy density functionals of becke and Lee, Yang and Parr
B. Miehlich (1989)
Protein Sci
R Armen (2003)
J Am Chem Soc
V Tsui (2000)
10.1093/bioinformatics/btg224
PISCES: a protein sequence culling server
G. Wang (2003)
10.1038/nature01160
Absolute comparison of simulated and experimental protein-folding dynamics
C. D. Snow (2002)
10.1021/J100007A062
Conductor-like Screening Model for Real Solvents: A New Approach to the Quantitative Calculation of Solvation Phenomena
A. Klamt (1995)
10.1016/S0006-3495(00)76411-3
High apparent dielectric constants in the interior of a protein reflect water penetration.
J. J. Dwyer (2000)
10.1021/JA0273851
All-atom structure prediction and folding simulations of a stable protein.
C. Simmerling (2002)
10.1016/S0022-2836(03)00177-3
Ab initio folding simulation of the Trp-cage mini-protein approaches NMR resolution.
Shibasish Chowdhury (2003)
10.1073/pnas.181328398
TOUCHSTONE: An ab initio protein structure prediction method that uses threading-based tertiary restraints
D. Kihara (2001)
Theochem-J Mol Struct
J Tomasi (1999)
J Am Chem Soc
C Simmerling (2002)
J Mol Biol
T E Cheatham (1996)
10.1073/PNAS.95.4.1562
Molecular picture of folding of a small α/β protein
F. Sheinerman (1998)
Curr Opin Struct Biol
E I Shakhnovich (1997)
Computer Simulations of Biological Systems
P A Kollman (1997)
10.1002/prot.10171
Distinguishing native conformations of proteins from decoys with an effective free energy estimator based on the OPLS all‐atom force field and the surface generalized born solvent model
A. K. Felts (2002)
10.1103/PHYSREVB.37.785
Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density.
Lee (1988)
10.1063/1.469990
Incorporation of solvent effects into density functional calculations of molecular energies and geometries
J. Andzelm (1995)
10.1021/BI9706677
Comparison of NH exchange and circular dichroism as techniques for measuring the parameters of the helix-coil transition in peptides.
C. Rohl (1997)
10.1021/JP994157T
Thermodynamics and Kinetics of Folding of Two Model Peptides Investigated by Molecular Dynamics Simulations
P. Ferrara (2000)
10.1016/S0166-1280(98)00553-3
The IEF version of the PCM solvation method: an overview of a new method addressed to study molecular solutes at the QM ab initio level
J. Tomasi (1999)
10.1063/1.472829
Treatment of the outlying charge in continuum solvation models
A. Klamt (1996)
J Phys Chem
A Klamt (1995)
10.4135/9781412952644.n56
“Bioinformatics” 특집을 내면서
장병탁 (2000)
Proc Natl Acad Sci
F B Sheinerman (1998)
10.1016/S0959-440X(97)80005-X
Theoretical studies of protein-folding thermodynamics and kinetics.
E. Shakhnovich (1997)
10.1063/1.474659
A new integral equation formalism for the polarizable continuum model: Theoretical background and applications to isotropic and anisotropic dielectrics
E. Cancès (1997)
10.1006/JMBI.1996.0330
Observation of the A-DNA to B-DNA transition during unrestrained molecular dynamics in aqueous solution.
T. Cheatham (1996)
10.1021/J100142A004
A well-behaved electrostatic potential-based method using charge restraints for deriving atomic char
Christian Baily (1993)
J Phys Chem B
G A Kaminski (2001)
Annu Rev Phys Chem
D Bashford (2000)
J Phys Chem B
M Feig (2003)
10.1103/PHYSREVB.57.R13985
Parallel replica method for dynamics of infrequent events
A. Voter (1998)
10.1073/PNAS.92.8.3190
Computer determination of peptide conformations in water: different roads to structure.
C. Simmerling (1995)
Theor Chem Acc
C S Pomelli (2001)
10.1002/BIP.10216
Breaking non-native hydrophobic clusters is the rate-limiting step in the folding of an alanine-based peptide.
Shibasish Chowdhury (2003)
J Am Chem Soc
C Simmerling (1998)



This paper is referenced by
10.1080/07391102.2016.1199972
Scrutiny of chain-length and N-terminal effects in α-helix folding: a molecular dynamics study on polyalanine peptides
Bhupesh Goyal (2017)
10.1038/srep37628
In Silico Exploration for Novel Type-I Inhibitors of Tie-2/TEK: The Performance of Different Selection Strategy in Selecting Virtual Screening Candidates
P. Pan (2016)
10.1016/BS.PMBTS.2019.05.007
Intrinsically disordered proteins in various hypotheses on the pathogenesis of Alzheimer's and Parkinson's diseases.
Orkid Coskuner (2019)
10.1016/j.ijpharm.2017.08.068
Prediction and characterization of the stability enhancing effect of the Cherry-Tag™ in highly concentrated protein solutions by complex rheological measurements and MD simulations.
P. Baumann (2017)
10.1039/c6mb00678g
Integrated discovery of FOXO1-DNA stabilizers from marine natural products to restore chemosensitivity to anti-EGFR-based therapy for metastatic lung cancer.
Yingjia Sun (2017)
10.3109/10799893.2015.1075040
Qualitative and quantitative pharmacophore-similarity assessment of anthranilamide-based factor Xa inhibitors: applications on similar molecules with identical biological endpoints
S. P. Kumar (2016)
10.1093/protein/gzv025
Designing a mutant CCL2-HSA chimera with high glycosaminoglycan-binding affinity and selectivity.
T. Gerlza (2015)
10.1002/jcc.24032
Probing the range of applicability of structure‐ and energy‐adjusted QM/MM link bonds
M. Hitzenberger (2015)
10.1080/07391102.2015.1032745
112 Structurally distinct ubiquitin- and SUMO-modified PCNA: implications for their distinct roles in the DNA damage response
S. Tsutakawa (2015)
10.1124/mol.116.105007
Extracellular Loop 2 of the Adenosine A1 Receptor Has a Key Role in Orthosteric Ligand Affinity and Agonist Efficacy
A. Nguyen (2016)
10.1021/acs.jctc.5b00911
Conformational Interconversions of Amino Acid Derivatives.
Jakub Kaminský (2016)
10.1016/j.molimm.2014.07.021
Coupling between side chain interactions and binding pocket flexibility in HLA-B*44:02 molecules investigated by molecular dynamics simulations.
Katja Ostermeir (2015)
10.1063/1.4890503
An atomic charge model for graphene oxide for exploring its bioadhesive properties in explicit water.
D. Stauffer (2014)
10.1101/2020.07.01.182725
DiffNets: deep learning the structural determinants of proteins biochemical properties by comparing different structural ensembles
M. D. Ward (2020)
10.3390/biom4030725
Local Order in the Unfolded State: Conformational Biases and Nearest Neighbor Interactions
Siobhan E Toal (2014)
10.1080/07391102.2020.1796802
Dual inhibitors of SARS-CoV-2 proteases: pharmacophore and molecular dynamics based drug repositioning and phytochemical leads
Kartik Mitra (2020)
10.1016/j.ijpharm.2019.03.057
High‐throughput computational pipeline for 3‐D structure preparation and in silico protein surface property screening: A case study on HBcAg dimer structures
Marieke E. Klijn (2019)
10.3390/molecules24122248
The Amphoteric and Hydrophilic Properties of Cartilage Surface in Mammalian Joints: Interfacial Tension and Molecular Dynamics Simulation Studies
K. Janicka (2019)
10.1021/ct7002258
Combining Elastic Network Analysis and Molecular Dynamics Simulations by Hamiltonian Replica Exchange.
M. Zacharias (2008)
10.1016/bs.pmbts.2019.12.009
Pairwise-additive and polarizable atomistic force fields for molecular dynamics simulations of proteins.
Justin A. Lemkul (2020)
10.1016/j.exger.2019.06.002
Early impairment of epigenetic pattern in neurodegeneration: Additional mechanisms behind pyrethroid toxicity
L. Bordoni (2019)
10.1142/S0219720018400152
Investigation of non-hydroxamate scaffolds against HDAC6 inhibition: A pharmacophore modeling, molecular docking, and molecular dynamics simulation approach
Amir Zeb (2018)
10.1007/s10989-019-09875-7
Studying Calcium Ion-Dependent Effect on the Inter-subunit Interaction Between the cTnC N-terminal Domain and cTnI C-terminal Switch Peptide of Human Cardiac Troponin via Chou’s 5-Steps Rule
W. Yu (2019)
10.1063/5.0011165
Analysis of properties of thermally deformed protein structure by using two different types of artificial intelligence
Katsuhiko Nishiyama (2020)
10.1021/acs.jpcb.7b03935
Orthogonal Electric Field Measurements near the Green Fluorescent Protein Fluorophore through Stark Effect Spectroscopy and pKa Shifts Provide a Unique Benchmark for Electrostatics Models.
J. Slocum (2017)
10.1002/wcms.1329
Reaction coordinates and transition states in enzymatic catalysis
Kirill Zinovjev (2018)
10.1002/psc.3057
Modeling of a C‐end rule peptide adsorbed onto gold nanoparticles
Jordi Triguero (2018)
10.1021/acscentsci.7b00465
Prediction of New Stabilizing Mutations Based on Mechanistic Insights from Markov State Models
M. Zimmerman (2017)
10.1529/BIOPHYSJ.106.082917
Unbinding of retinoic acid from the retinoic acid receptor by random expulsion molecular dynamics.
P. Carlsson (2006)
Interactions of carbon nanotubes and lipid bilayers
Wojciech Rzepala (2013)
10.1007/s00044-016-1712-x
Identification of potent inhibitors for chromodomain-helicase- DNA-binding protein 1-like through moleculardocking studies
Sundus Iqbal (2016)
10.1021/JM061158I
Mechanism of drug resistance due to N88S in CRF01_AE HIV-1 protease, analyzed by molecular dynamics simulations.
H. Ode (2007)
See more
Semantic Scholar Logo Some data provided by SemanticScholar