ABSTRACT: We propose a new way of looking at global optimization of off-lattice protein
models. We present a dual optimization concept of predicting optimal sequences
as well as optimal folds. We validate the utility of the recently introduced
hidden-force Monte Carlo optimization algorithm by finding significantly lower
energy folds for minimalist protein models than previously reported. Further,
we also find the protein sequence that yields the lowest energy fold amongst
all sequences for a given chain length and residue mixture. In particular, for
protein models with a binary sequence, we show that the sequence-optimized
folds form more compact cores than the lowest energy folds of the historically
fixed, Fibonacci-series sequences of chain lengths of 13, 21, 34, 55, and 89.
We emphasize that while the protein model we used is minimalist, the
methodology is applicable to detailed protein models, and sequence optimization
may yield novel folds and aid de novo protein design.
ABSTRACT: We present a method for minimizing additive potential-energy functions. Our hidden-force algorithm can be described as an intricate multiplayer tug-of-war game in which teams try to break an impasse by randomly assigning some players to drop their ropes while the others are still tugging until a partial impasse is reached, then, instructing the dropouts to resume tugging, for all teams to come to a new overall impasse. Utilizing our algorithm in a non-Markovian parallel Monte Carlo search, we found 17 new putative global minima for binary Lennard-Jones clusters in the size range of 90-100 particles. The method is efficient enough that an unbiased search was possible; no potential-energy surface symmetries were exploited. All new minima are comprised of three nested polyicosahedral or polytetrahedral shells when viewed as a nested set of Connolly surfaces (though the shell structure has previously gone unscrutinized, known minima are often qualitatively similar). Unlike known minima, in which the outer and inner shells are comprised of the larger and smaller atoms, respectively, in 13 of the new minima, the atoms are not as clearly separated by size. Furthermore, while some known minima have inner shells stabilized by larger atoms, four of the new minima have outer shells stabilized by smaller atoms.
Physical Review E 11/2010; 82(5 Pt 2):056711. · 2.26 Impact Factor
ABSTRACT: Na+/H+ antiporters are central to cellular salt and pH homeostasis. The structure of Escherichia coli NhaA was recently determined, but its mechanisms of transport and pH regulation remain elusive. We performed molecular dynamics simulations of NhaA that, with existing experimental data, enabled us to propose an atomically detailed model of antiporter function. Three conserved aspartates are key to our proposed mechanism: Asp164 (D164) is the Na+-binding site, D163 controls the alternating accessibility of this binding site to the cytoplasm or periplasm, and D133 is crucial for pH regulation. Consistent with experimental stoichiometry, two protons are required to transport a single Na+ ion: D163 protonates to reveal the Na+-binding site to the periplasm, and subsequent protonation of D164 releases Na+. Additional mutagenesis experiments further validated the model.
Science 09/2007; 317(5839):799-803. · 31.20 Impact Factor
Proceedings of the ACM/IEEE SC2006 Conference on High Performance Networking and Computing, November 11-17, 2006, Tampa, FL, USA; 01/2006
ABSTRACT: Cyclodextrin derivatives can increase the enzymatic hydrolysis of triolein in aqueous solution. Two types of cyclodextrin inclusion complexes could be responsible for this effect. In the present study, molecular dynamics simulations clearly suggest that cyclodextrin hosts only the liberated fatty acid thus accelerating lipolysis by decreasing product inhibition.
Biotechnology Letters 03/1996; 18(4):440-444. · 1.68 Impact Factor