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Configurational temperature density of states simulations of proteins.

ABSTRACT: A novel method has been implemented to compute the density of states of proteins. A united atom representation and the CHARMM (Brooks et al., 1983) force-field parameters have been adopted for all the simulations. In this approach, an intrinsic temperature is computed based on configurational information about the protein. A random walk is performed in potential energy space and the configurational temperature is collected as a function of potential energy of the system. The density of states is then calculated by integrating the reciprocal of temperature. Unlike previously available methods, this approach does not involve calculations based on histograms of stochastic visits to distinct energy states. It is found that the proposed method is more efficient than earlier, related schemes for simulation of protein folding. Furthermore, it directly provides thermodynamic information, including free energies. The usefulness of the method is discussed by presenting results of simulations of the 16-residue beta-hairpin taken from the C-terminal fragment (41-56) of protein G.

SUBMITTER: Rathore N

PROVIDER: S-EPMC1303697 | biostudies-literature | 2003 Dec

REPOSITORIES: biostudies-literature

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Configurational temperature density of states simulations of proteins.

Rathore Nitin N Knotts Thomas A TA de Pablo Juan J JJ

Biophysical journal 20031201 6

A novel method has been implemented to compute the density of states of proteins. A united atom representation and the CHARMM (Brooks et al., 1983) force-field parameters have been adopted for all the simulations. In this approach, an intrinsic temperature is computed based on configurational information about the protein. A random walk is performed in potential energy space and the configurational temperature is collected as a function of potential energy of the system. The density of states is ...[more]

PMID: 14645085

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Project description:The adenosylcobalamin- (coenzyme B12) dependent ethanolamine ammonia-lyase (EAL) plays a key role in aminoethanol metabolism, associated with microbiome homeostasis and Salmonella- and Escherichia coli-induced disease conditions in the human gut. To gain molecular insight into these processes toward development of potential therapeutic targets, reactions of the cryotrapped (S)-2-aminopropanol substrate radical EAL from Salmonella typhimurium are addressed over a temperature (T) range of 220-250 K by using T-step reaction initiation and time-resolved, full-spectrum electron paramagnetic resonance spectroscopy. The observed substrate radical reaction kinetics are characterized by two pairs of biexponential processes: native decay to diamagnetic products and growth of a non-native radical species and Co(II) in cobalamin. The multicomponent low-T kinetics are simulated by using a minimal model, in which the substrate-radical macrostate, S?, is partitioned by a free-energy barrier into two sequential microstates: 1) S1?, a relatively high-entropy/high-enthalpy microstate with a protein configuration that captures the nascent substrate radical in the terminal step of radical-pair separation; and 2) S2?, a relatively low-enthalpy/low-entropy microstate with a protein configuration that enables the rearrangement reaction. The non-native, destructive reaction of S1? at T ? 250 K is caused by a prolonged lifetime in the substrate-radical capture state. Monotonic S? decay over 278-300 K indicates that the free-energy barrier to S1? and S2? interconversion is latent at physiological T-values. Overall, the low-temperature studies reveal two protein-configuration microstates and connecting protein-configurational transitions that specialize the S? macrostate for the dual functional roles of radical capture and rearrangement enabling. The identification of new, to our knowledge, intermediate states and specific protein-fluctuation contributions to the reaction coordinate represent an advance toward development of novel therapeutic targets in EAL.

Dataset Information

Configurational temperature density of states simulations of proteins.

Publications

Configurational temperature density of states simulations of proteins.

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