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Structural Survey of Zinc Containing Proteins and the Development of the Zinc AMBER Force Field (ZAFF).

ABSTRACT: Currently the Protein Data Bank (PDB) contains over 18,000 structures that contain a metal ion including Na, Mg, K, Ca, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Pd, Ag, Cd, Ir, Pt, Au, and Hg. In general, carrying out classical molecular dynamics (MD) simulations of metalloproteins is a convoluted and time consuming process. Herein, we describe MCPB (Metal Center Parameter Builder), which allows one, to conveniently and rapidly incorporate metal ions using the bonded plus electrostatics model (Hoops et al., J. Am. Chem. Soc. 1991, 113, 8262-8270) into the AMBER Force Field (FF). MCPB was used to develop a Zinc FF, ZAFF, which is compatible with the existing AMBER FFs. The PDB was mined for all Zn containing structures with most being tetrahedrally bound. The most abundant primary shell ligand combinations were extracted and FFs were created. These include Zn bound to CCCC, CCCH, CCHH, CHHH, HHHH, HHHO, HHOO, HOOO, HHHD, and HHDD (O = water and the remaining are 1 letter amino acid codes). Bond and angle force constants and RESP charges were obtained from B3LYP/6-31G* calculations of model structures from the various primary shell combinations. MCPB and ZAFF can be used to create FFs for MD simulations of metalloproteins to study enzyme catalysis, drug design and metalloprotein crystal refinement.

SUBMITTER: Peters MB

PROVIDER: S-EPMC2941202 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Structural Survey of Zinc Containing Proteins and the Development of the Zinc AMBER Force Field (ZAFF).

Peters Martin B MB Yang Yue Y Wang Bing B Füsti-Molnár László L Weaver Michael N MN Merz Kenneth M KM

Journal of chemical theory and computation 20100901 9

Currently the Protein Data Bank (PDB) contains over 18,000 structures that contain a metal ion including Na, Mg, K, Ca, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Pd, Ag, Cd, Ir, Pt, Au, and Hg. In general, carrying out classical molecular dynamics (MD) simulations of metalloproteins is a convoluted and time consuming process. Herein, we describe MCPB (Metal Center Parameter Builder), which allows one, to conveniently and rapidly incorporate metal ions using the bonded plus electrostatics model (Hoops et al ...[more]

PMID: 20856692

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Project description:The utility of molecular dynamics (MD) simulations to model biomolecular structure, dynamics, and interactions has witnessed enormous advances in recent years due to the availability of optimized MD software and access to significant computational power, including GPU multicore computing engines and other specialized hardware. This has led researchers to routinely extend conformational sampling times to the microsecond level and beyond. The extended sampling time has allowed the community not only to converge conformational ensembles through complete sampling but also to discover deficiencies and overcome problems with the force fields. Accuracy of the force fields is a key component, along with sampling, toward being able to generate accurate and stable structures of biopolymers. The Amber force field for nucleic acids has been used extensively since the 1990s, and multiple artifacts have been discovered, corrected, and reassessed by different research groups. We present a direct comparison of two of the most recent and state-of-the-art Amber force field modifications, bsc1 and OL15, that focus on accurate modeling of double-stranded DNA. After extensive MD simulations with five test cases and two different water models, we conclude that both modifications are a remarkable improvement over the previous bsc0 force field. Both force field modifications show better agreement when compared to experimental structures. To ensure convergence, the Drew-Dickerson dodecamer (DDD) system was simulated using 100 independent MD simulations, each extended to at least 10 ?s, and the independent MD simulations were concatenated into a single 1 ms long trajectory for each combination of force field and water model. This is significantly beyond the time scale needed to converge the conformational ensemble of the internal portions of a DNA helix absent internal base pair opening. Considering all of the simulations discussed in the current work, the MD simulations performed to assess and validate the current force fields and water models aggregate over 14 ms of simulation time. The results suggest that both the bsc1 and OL15 force fields render average structures that deviate significantly less than 1 Å from the average experimental structures. This can be compared to similar but less exhaustive simulations with the CHARMM 36 force field that aggregate to the ?90 ?s time scale and also perform well but do not produce structures as close to the DDD NMR average structures (with root-mean-square deviations of 1.3 Å) as the newer Amber force fields. On the basis of these analyses, any future research involving double-stranded DNA simulations using the Amber force fields should employ the bsc1 or OL15 modification.

Dataset Information

Structural Survey of Zinc Containing Proteins and the Development of the Zinc AMBER Force Field (ZAFF).

Publications

Structural Survey of Zinc Containing Proteins and the Development of the Zinc AMBER Force Field (ZAFF).

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