Computer simulation of biological interactions and reactivity

Computer simulations of molecular motion provide a useful tool for analyzing dynamic aspects of macromolecular structure and function. In many cases, simulations can be compared to experimental results that provide an average estimate of molecular flexibility. For example, variations in computed molecular motions in different regions of a protein structure can be compared to refined B-values obtained from X-ray crystallographic refinement. Such comparisons both provide a detailed view of the motions responsible for crystalline disorder, and allow an evaluation of how crystal packing affects mobility of groups on the protein surface. In these applications, dynamics simulations provide a means of regenerating the temporal dimension of a structure whose average behavior is experimentally well defined in the crystal lattice. An additional benefit of the detailed and instantaneous view of molecular flexibility offered by simulation methods lies in its potential for exploring infrequent structural fluctuations or dynamic states of molecular association that cannot be examined in detail by X-ray methods, but are suggested on the basis of alternative structural information. For example, studies of the effects of surface chemical modification on interacting proteins can produce information concerning the sites, if not the exact details, of the intermolecular interactions. The present work describes some applications of molecular dynamics methods to the study of large molecular aggregates whose dynamic properties thus far have precluded detailed structural descriptions. These include simulations of an electrostatically associated electron transfer complex between cytochromes c and b5, some model systems for trans-membrane ion channels, and a phospholipid micelle.