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Placevent: An algorithm for prediction of explicit solvent atom distribution—Application to HIV-1 protease and F-ATP synthase

Sindhikara, D. J., Yoshida, N. and Hirata, F. 133, 18 (2012) 1536-1543, Placevent: An algorithm for prediction of explicit solvent atom distribution—Application to HIV-1 protease and F-ATP synthase. J. Comput. Chem.. doi: 10.1002/jcc.22984


We have created a simple algorithm for automatically predicting the explicit solvent atom distribution of biomolecules. The explicit distribution is coerced from the three-dimensional (3D) continuous distribution resulting from a 3D reference interaction site model (3D-RISM) calculation. This procedure predicts optimal location of solvent molecules and ions given a rigid biomolecular structure and the solvent composition. We show examples of predicting water molecules near the KNI-272 bound form of HIV-1 protease and predicting both sodium ions and water molecules near the rotor ring of F-adenosine triphosphate (ATP) synthase. Our results give excellent agreement with experimental structure with an average prediction error of 0.39–0.65 Å. Further, unlike experimental methods, this method does not suffer from the partial occupancy limit. Our method can be performed directly on 3D-RISM output within minutes. It is extremely useful for examining multiple specific solvent–solute interactions, as a convenient method for generating initial solvent structures for molecular dynamics calculations, and may assist in refinement of experimental structures.

Modular reweighting software for statistical mechanical analysis of biased equilibrium data
D.J. Sindhikara. Computer Physics Communications, 182 (2011) 2227–2231

(Research Article/Computer Program)

Here a simple, useful, modular approach and software suite designed for statistical reweighting and analysis of equilibrium ensembles is presented. Statistical reweighting is useful and sometimes necessary for analysis of equilibrium enhanced sampling methods, such as umbrella sampling or replica exchange, and also in experimental cases where biasing factors are explicitly known. Essentially, statistical reweighting allows extrapolation of data from one or more equilibrium ensembles to another. Here, the fundamental separable steps of statistical reweighting are broken up into modules – allowing for application to the general case and avoiding the black-box nature of some “all-inclusive” reweighting programs. Additionally, the programs included are, by-design, written with little dependencies. The compilers required are either pre-installed on most systems, or freely available for download with minimal trouble. Examples of the use of this suite applied to umbrella sampling and replica exchange molecular dynamics simulations will be shown along with advice on how to apply it in the general case.

Solvent penetration in photoactive yellow protein R52Q mutant: A theoretical study
D.J. Sindhikara, N. Yoshida, M. Kataoka & F. Hirata. Journal of Molecular Liquids,  164 (1-2), 120 (2011)

(Research Article)

An R52Q mutation of photoactive yellow protein creates a cavity mimicking an intermediate state in the wild-type. This mutation, of a positively charged arginine to a neutral glutamine, does not affect the spectral tuning of photoactive yellow protein. Contradicting explanations for this phenomenon suggest either water or hydronium occupation in the cavity. To solve this controversy, we have performed 3D-RISM calculations on the mutant structure examining the solvation structure. Our results show that while there is a high probability of hydronium in the cavity compared to bulk, there is still a relatively low occupation when considering realistic concentrations. Thus our findings suggest that while the cavity is clearly accessible by hydronium, it is mostly occupied by water molecules. We expect high-resolution neutron crystallographic analysis of the mutant to confirm our prediction.

Exchange Often and Properly in Replica Exchange Molecular Dynamics
D.J. Sindhikara, D.J. Emerson, & A.E. Roitberg,
J. Chem. Theory Comput., 2010, 6(9), 2804-2808.

(Research Article)

  Previous work by us showed that in replica exchange molecular dynamics, exchanges should be attempted extremely often, providing gains in efficiency and no undesired effects. Since that time some questions have been raised about the extendability of these claims to the general case. In this work, we answer this question in two ways. First, we perform a study measuring the effect of exchange attempt frequency in explicit solvent simulations including thousands of atoms. This shows, consistent with the previous assertion, that high exchange attempt frequency allows an optimal rate of exploration of configurational space. Second, we present an explanation of many theoretical and technical pitfalls when implementing replica exchange that cause “improper” exchanges resulting in erroneous data, exacerbated by high exchange attempt frequency.

Apo and
Nickel-bound Forms of the Pyrococcus Horikoshii Species of the Metalloregulatory Protein: NikR Characterized by Molecular Dynamics Simulations
D.J. Sindhikara, A.E. Roitberg, K.M. Merz Jr, Biochemistry, 2009, 48 (50), pp 12024–12033

(Research Article)

NikR is a homotetrameric nickel regulatory protein whose binding to free Ni2+ increases its binding affinity for a gene that codes for a nickel transporter protein. It is comprised of a tetrameric nickel-binding domain, flanked by two dimeric DNA-binding domains. Though X-ray crystallography data for various species (Escherichia coli, Heliobacter pylori, and Pyrococcus horikoshii) of NikR reveal large conformational differences between nickel-bound, DNA-bound, and unbound forms, transitions between them have never been observed. We have run all-atom molecular dynamics simulations of three forms of the Pyrococcus horikoshii species of NikR including two apo-forms and one nickel-bound form. Though all 552 residues of this species occur naturally, quantum-mechanics-based force-field parametrization was required to accurately represent the four nickel-centers in the nickel-bound form. Global conformational analysis of the three 100-ns-long simulations indicates slow conformational kinetics and independent DNA binding domain motion. Correlation and flexibility analysis revealed regions of high structural and dynamical importance. A striking relationship was observed between regions with high levels of structural importance and regions with known biological importance. Mutation of key regions of P. horikoshii and analogous regions in both E. coli and H. pylori are suggested that might inhibit DNA-binding activity while not affecting nickel-binding.

Bad Seeds Sprout Perilous Dynamics: Stochastic Thermostat Induced Trajectory Synchronization of Biomolecules
D. Sindhikara, S. Kim, A.F. Voter, A. Roitberg,
J. Chem. Theory Comput. 5, 1624 (2009)
(Research Article)
    Molecular dynamics simulations starting from different initial conditions are commonly used to mimic the behavior of an experimental ensemble. We show in this article that when a Langevin thermostat is used to maintain constant temperature during such simulations, extreme care must be taken when choosing the random number seeds to prevent statistical correlation among the MD trajectories. While recent studies have shown that stochastically thermostatted trajectories evolving within a single potential basin with identical random number seeds tend to synchronize, we show that there is a synchronization effect even for complex, biologically relevant systems. We demonstrate this effect in simulations of alanine trimer and pentamer and in a simulation of a temperature-jump experiment for peptide folding of a 14-residue peptide. Even in replica-exchange simulations, in which the trajectories are at different temperatures, we find partial synchronization occurring when the same random number seed is employed. We explain this by extending the recent derivation of the synchronization effect for two trajectories in a harmonic well to the case in which the trajectories are at two different temperatures. Our results suggest several ways in which mishandling selection of a pseudorandom number generator initial seed can lead to corruption of simulation data. Simulators can fall into this trap in simple situations such as neglecting to specifically indicate different random seeds in either parallel or sequential restart simulations, utilizing a simulation package with a weak pseudorandom number generator, or using an advanced simulation algorithm that has not been programmed to distribute initial seeds.

Exchange frequency in replica exchange molecular dynamics
D. Sindhikara, Yilin Meng, and Adrian E. Roitberg
, J. Chem. Phys. 128, 024103 (2008)

(Research Article)

    The effect of the exchange-attempt frequency on sampling efficiency is studied in replica exchange molecular dynamics (REMD). We show that sampling efficiency increases with increasing exchange-attempt frequency. This conclusion is contrary to a commonly expressed view in REMD. Five peptides (1–21 residues long) are studied with a spectrum of exchange-attempt rates. Convergence rates are gauged by comparing ensemble properties between fixed length test REMD simulations and longer reference simulations. To show the fundamental correlation between exchange frequency and convergence time, a simple model is designed and studied, displaying the same basic behavior of much more complex systems.

A Sampling of Molecular Dynamics
D. J. Sindhikara, University of Florida, (2009)



    The sheer vastness of the number of computations required to simulate a biological molecule puts incredible pressure on algorithms to be efficient while maintaining sufficient accuracy. This dissertation summarizes various projects whose purposes address the large span of types of problems in molecular dynamics simulations of biological systems including: increasing efficiency, measuring convergence, avoiding pitfalls, and an application and analysis of a biological system. Chapters 3 and 4 deal with an enhanced sampling algorithm called “replica exchange molecular dynamics” which is designed to speed-up molecular dynamics simulations. The optimization of a key parameter of these simulations is analyzed. In these successive projects, it was found conclusively that maximizing “exchange attempt frequency” is the most efficient way to run a replica exchange molecular dynamics simulation. Chapter 5 describes an enhanced metric for convergence in parallel simulations called the normalized ergodic measure. The metric is applied to several properties for several replica exchange simulations. Advantages of this metric over other methods are described. Chapter 6 describes the implementation and optimization of an enhanced sampling algorithm similar to replica exchange molecular dynamics called multicanonical algorithm replica exchange molecular dynamics. The algorithm was implemented into a biomolecular simulation suite called AMBER. Additionally several parameters were analyzed and optimized. In Chapter 7, a pitfall in molecular dynamics is observed in biological systems that is caused by negligent use of a simulation’s “thermostat”. It was found that if the same pseudorandom number seed were used for multiple systems, they eventually synchronize. In this project, synchronization was observed in biological molecules. Various negative effects including corruption of data are pointed out. Chapter 8 describes molecular dynamics simulation of NikR, a homotetrameric nickel regulatory protein whose binding to free Ni++ increases its binding affinity for a nickel transporter gene. Three forms of the Pyrococcus Horikoshii species of NikR were simulated including two apo-forms and one nickel-bound form. A quantum-mechanics-based force field parameterization was required to accurately represent the four nickel-centers in the holo-form. Extensive analysis of the three 100-ns-long trajectories was performed.