John M. Rosenberg

Abstract The Weighted Histogram Analysis Method (WHAM), an extension of Ferrenberg and Swendsen's Multiple Histogram Technique, has been applied for the first time on complex biomolecular Hamiltonians. The method is presented here as an extension of the Umbrella Sampling method for free‐energy and Potential of Mean Force calculations. This algorithm possesses the following advantages over methods that are currently employed: (1) It provides a built‐in estimate of sampling errors thereby yielding objective estimates of the optimal location and length of additional simulations needed to achieve a desired level of precision; (2) it yields the “best” value of free energies by taking into account all the simulations so as to minimize the statistical errors; (3) in addition to optimizing the links between simulations, it also allows multiple overlaps of probability distributions for obtaining better estimates of the free‐energy differences. By recasting the Ferrenberg–Swendsen Multiple Histogram equations in a form suitable for molecular mechanics type Hamiltonians, we have demonstrated the feasibility and robustness of this method by applying it to a test problem of the generation of the Potential of Mean Force profile of the pseudorotation phase angle of the sugar ring in deoxyadenosine. © 1992 by John Wiley & Sons, Inc.

The base pairs in double helical nucleic acids have been compared to see how they can be recognized by proteins. We conclude that a single hydrogen bond is inadequate for uniquely identifying any particular base pair, as this leads to numerous degeneracies. However, using two hydrogen bonds, fidelity of base pair recognition may be achieved. We propose specific amino-acid side chain interactions involving two hydrogen bonds as a component of the recognition system for base pairs. In the major groove we suggest that asparagine or glutamine binds to adenine of the base pair or arginine binds to guanine. In the minor groove, we suggest an interaction between asparagine or glutamine with guanine of the base pair. We also discuss the role that ions and other amino-acid side chains may play in recognition interactions.

Abstract The recently formulated weighted histogram analysis method (WHAM) 1 is an extension of Ferrenberg and Swendsen's multiple histogram technique for free‐energy and potential of mean force calculations. As an illustration of the method, we have calculated the two‐dimensional potential of mean force surface of the dihedrals gamma and chi in deoxyadenosine with Monte Carlo simulations using the all‐atom and united‐atom representation of the AMBER force fields. This also demonstrates one of the major advantages of WHAM over umbrella sampling techniques. The method also provides an analysis of the statistical accuracy of the potential of mean force as well as a guide to the most efficient use of additional simulations to minimize errors. © 1995 John Wiley & Sons, Inc.

The crystal structure of the complex between Eco RI endonuclease and the cognate oligonucleotide TCGCGAATTCGCG provides a detailed example of the structural basis of sequence-specific DNA-protein interactions. The structure was determined, to 3 Å resolution, by the ISIR (iterative single isomorphous replacement) method with a platinum isomorphous derivative. The complex has twofold symmetry. Each subunit of the endonuclease is organized into an α/β domain consisting a five-stranded β sheet, α helices, and an extension, called the "arm," which wraps around the DNA. The large β sheet consists of antiparallel and parallel motifs that form the foundations for the loops and α helices responsible for DNA strand scission and sequence-specific recognition, respectively. The DNA cleavage site is located in a cleft that binds the DNA backbone in the vicinity of the scissile bond. Sequence specificity is mediated by 12 hydrogen bonds originating from α helical recognition modules. Arg 200 forms two hydrogen bonds with guanine while Glu 144 and Arg 145 form four hydrogen bonds to adjacent adenine residues. These interactions discriminate the Eco RI hexanucleotide GAATTC from all other hexanucleotides because any base substitution would require rupture of at least one of these hydrogen bonds.