With the increased availability of parallel computer resources amenable to large scale scientific computing, it is essential to optimize the use of these resources. The primary efforts include the development of parallel computing techniques suitable for macromolecular simulation and the development of a parallel computer cluster and related software for high-efficiency simulations at low cost. Current projects include: - LoBoS: High performance computing using PC clusters - Development of parallel QM/MM methods, Replica/Path - Development of bioinformatics tools for PC clusters - Development and evaluation of parallel algorithms for molecular dynamics - Development and support of parallel CHARMM - Development of Latency-tolerant algorithms for Parallel Computing The LoBoS (Lots of Boxes on Shelves), LoBoSIII (and pending LoBoSIV/Biowulf III) supercomputers have been designed and constructed using commodity PCs. They provide a greater than 10-fold improvement in price/performance when compared with the traditional supercomputer vendor's offerings. The early LoBoS systems demonstrated the effectiveness of this approach and were essential in the development of techniques and linux scripts. LoBoS IV will be a substantial improvement in that over 600 processors will be setup. The LoBoS Project has produced the most capable computational system at the NIH for most applications involving computational chemistry tools. It has opened up a new realm of high performance computing which continues to drive the cost down while improving reliability through the use of loosely-coupled clusters. The main effort in developing new bioinformatics tools for the PC cluster environemnt is the development of a new architecture for the integration of disparate biological databases and for the distribution of compute-intensive tasks. Clusters are uniquely suited to large database applications since each compute node has its own disk (maximizing IO) and its workload may be configured to be independent of other nodes (maximizing efficiency). This work is now part of our ongoing efforts to support the NHLBI Bioinformatics Core Facility. In addition to work on clusters, CHARMM has been modified to support the teraflop GRAPE-2 PC enhancement board from RIKEN (Japan). This board allows the very rapid computation of long-range electrostatic and van der Waal interactions. As part of the development of the Replica/Path QM/MM method, we have created a novel way to parallelize these large scale quantum part of these calculations involving MPI clusters.