Asim Okur

Comparison of multiple Amber force fields and development of improved protein backbone parameters.

The ff94 force field that is commonly associated with the Amber simulation package is one of the most widely used parameter sets for biomolecular simulation. After a decade of extensive use and testing, limitations in this force field, such as over‐stabilization of α‐helices, were reported by us and other researchers. This led to a number of attempts to improve these parameters, resulting in a variety of “Amber” force fields and significant difficulty in determining which should be used for a particular application. We show that several of these continue to suffer from inadequate balance between different secondary structure elements. In addition, the approach used in most of these studies neglected to account for the existence in Amber of two sets of backbone φ/ψ dihedral terms. This led to parameter sets that provide unreasonable conformational preferences for glycine. We report here an effort to improve the φ/ψ dihedral terms in the ff99 energy function. Dihedral term parameters are based on fitting the energies of multiple conformations of glycine and alanine tetrapeptides from high level ab initio quantum mechanical calculations. The new parameters for backbone dihedrals replace those in the existing ff99 force field. This parameter set, which we denote ff99SB, achieves a better balance of secondary structure elements as judged by improved distribution of backbone dihedrals for glycine and alanine with respect to PDB survey data. It also accomplishes improved agreement with published experimental data for conformational preferences of short alanine peptides and better accord with experimental NMR relaxation data of test protein systems. Proteins 2006.

Evaluating the Performance of the ff99SB Force Field Based on NMR Scalar Coupling Data

Force-field validation is essential for the identification of weaknesses in current models and the development of more accurate models of biomolecules. NMR coupling and relaxation methods have been used to effectively diagnose the strengths and weaknesses of many existing force fields. Studies using the ff99SB force field have shown excellent agreement between experimental and calculated order parameters and residual dipolar calculations. However, recent studies have suggested that ff99SB demonstrates poor agreement with J-coupling constants for short polyalanines. We performed extensive replica-exchange molecular-dynamics simulations on Ala(3) and Ala(5) in TIP3P and TIP4P-Ew solvent models. Our results suggest that the performance of ff99SB is among the best of currently available models. In addition, scalar coupling constants derived from simulations in the TIP4P-Ew model show a slight improvement over those obtained using the TIP3P model. Despite the overall excellent agreement, the data suggest areas for possible improvement.

Improved Efficiency of Replica Exchange Simulations through Use of a Hybrid Explicit/Implicit Solvation Model

The use of parallel tempering or replica exchange molecular dynamics (REMD) simulations has facilitated the exploration of free energy landscapes for complex molecular systems, but application to large systems is hampered by the scaling of the number of required replicas with increasing system size. Use of continuum solvent models reduces system size and replica requirements, but these have been shown to provide poor results in many cases, including overstabilization of ion pairs and secondary structure bias. Hybrid explicit/continuum solvent models can overcome some of these problems through an explicit representation of water molecules in the first solvation shells, but these methods typically require restraints on the solvent molecules and show artifacts in water properties due to the solvation interface. We propose an REMD variant in which the simulations are performed with a fully explicit solvent, but the calculation of exchange probability is carried out using a hybrid model, with the solvation shells calculated on the fly during the fully solvated simulation. The resulting reduction in the perceived system size in the REMD exchange calculation provides a dramatic decrease in the computational cost of REMD, while maintaining a very good agreement with results obtained from the standard explicit solvent REMD. We applied several standard and hybrid REMD methods with different solvent models to alanine polymers of 1, 3, and 10 residues, obtaining ensembles that were essentially independent of the initial conformation, even with explicit solvation. Use of only a continuum model without a shell of explicit water provided poor results for Ala3 and Ala10, with a significant bias in favor of the α-helix. Likewise, using only the solvation shells and no continuum model resulted in ensembles that differed significantly from the standard explicit solvent data. Ensembles obtained from hybrid REMD are in very close agreement with explicit solvent data, predominantly populating polyproline II conformations. Inclusion of a second shell of explicit solvent was found to be unnecessary for these peptides.

Using PC clusters to evaluate the transferability of molecular mechanics force fields for proteins

The transferability of molecular mechanics parameters derived for small model systems to larger biopolymers such as proteins can be difficult to assess. Even for small peptides, molecular dynamics simulations are typically too short to sample structures significantly different than initial conformations, making comparison to experimental data questionable. We employed a PC cluster to generate large numbers of native and non‐native conformations for peptides with experimentally measured structural data, one predominantly helical and the other forming a β‐hairpin. These atomic‐detail sets do not suffer from slow convergence, and can be used to rapidly evaluate important force field properties. In this case a suspected bias toward α‐helical conformations in the ff94 and ff99 force fields distributed with the AMBER package was verified. The sets provide critical feedback not only on force field transferability, but may also predict modifications for improvement. Such predictions were used to modify the ff99 parameter set, and the resulting force field was used to test stability and folding of model peptides. Structural behavior during molecular dynamics with the modified force field is found to be very similar to expectations, suggesting that these basis sets of conformations may themselves have significant transferability among force fields. We continue to improve and expand this data set and plan to make it publicly accessible. The calculations involved in this process are trivially parallel and can be performed using inexpensive personal computers with commodity components.

Improving Convergence of Replica-Exchange Simulations through Coupling to a High-Temperature Structure Reservoir.

Parallel tempering or replica-exchange molecular dynamics (REMD) significantly increases the efficiency of conformational sampling for complex molecular systems. However, obtaining converged data with REMD remains challenging, especially for large systems with complex topologies. We propose a new variant to REMD where the replicas are also permitted to exchange with an ensemble of structures that have been generated in advance using high-temperature MD simulations, similar in spirit to J-walking methods. We tested this approach on two non-trivial model systems, a β-hairpin and a 3-stranded β-sheet and compared the results to those obtained from very long (>100 ns) standard REMD simulations. The resulting ensembles were indistinguishable, including relative populations of different conformations on the unfolded state. The use of the reservoir is shown to significantly reduce the time required for convergence.

Evaluation of Salt Bridge Structure and Energetics in Peptides Using Explicit, Implicit, and Hybrid Solvation Models

Replica exchange or parallel tempering molecular dynamics (REMD) is widely used to enhance the exploration of free energy landscapes for complex molecular systems. However its application to large systems is hampered by the scaling of the number of required replicas with an increasing system size. We recently proposed an improved REMD method where the exchange probabilities were calculated using a hybrid explicit/implicit solvent model. We previously tested this hybrid solvent REMD approach on alanine polypeptides of 1, 3, and 10 residues and obtained very good agreement with fully solvated REMD simulations while significantly reducing the number of replicas required. In this study we continue evaluating the applicability of the hybrid solvent REMD method through comparing the free energy of formation of ion pairs using model peptides. In accord with other studies, pure GB simulations resulted in overstabilized salt bridges, whereas the hybrid models produced free energy profiles in close agreement with fully solvated simulations, including solvent separated minima. Furthermore, the structure of the salt bridge in explicit solvent is reproduced by the hybrid solvent REMD method, while the GB simulations favor a different geometry.

Improving the description of salt bridge strength and geometry in a Generalized Born model.

The Generalized Born (GB) solvent model is widely used in molecular dynamics simulations because it can be less computationally expensive and it samples conformational changes more efficiently than explicit solvent simulations. Meanwhile, great efforts have been made in the past to improve its precision and accuracy. Previous studies have shown that reducing intrinsic GB radii of some hydrogen atoms would improve AMBER GB-HCT solvent models accuracy on salt bridges. Here we present our finding that similar correction also shows dramatic improvement for the AMBER GB-OBC solvent model. Potential of mean force and cluster analysis for small peptide replica exchange molecular dynamics simulations suggested that new radii GB simulation with ff99SB/GB-OBC corrected salt bridge strength and achieved significantly higher geometry similarity with TIP3P simulation. Improved performance in 60 ns HIV-1 protease GB simulation further validated this approach for large systems.

Chapter 6 Hybrid Explicit/Implicit Solvation Methods

Publisher Summary This chapter describes a recent method that draws on ideas from these hybrid shell methods to reduce the computational cost of replica exchange molecular dynamics (REMD), an enhanced sampling method that has gained popularity for peptide and small protein folding studies. The chapter focuses on the hybrid shell approaches and briefly summarizes recent progress in this area. The hybrid shell method does not reduce the size of the simulated system, such as the solvent shell methods during dynamics, but the number of replicas required for the overall REMD simulation is reduced. Shell methods reduce system size by explicitly including solvent molecules only for the first 1–2 solvent shells and can be extremely useful in studies requiring extensive conformational sampling at a reduced cost. However, current implementations may not yet be ready for the simulation of large-scale conformational changes, because the number of water molecules in the solvent shell depends strongly on solute conformation. Hybrid solvation can be used with other methods to improve computational efficiency as seen with REMD simulations using hybrid exchange potential.